Antiinflammation agents

ABSTRACT

Compounds, compositions and methods that are useful in the treatment of inflammatory, immunoregulatory, metabolic, infectious and cell proliferative diseases or conditions are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, metabolism, infection and cell proliferation. The subject compounds contain a fused heterobicyclic ring.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/422,531, filed Oct. 31, 2002 (entitled “Antiinflammation Agents”Ref. No. T02-008-2/US), the contents of which is incorporated herein byreference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH OR DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK NOT APPLICABLE BACKGROUNDOF THE INVENTION

Tumor Necrosis Factor (TNF) and interleukin-1 (IL-1) are cytokines thathave been implicated in a wide range of biological processes, includinginflammation. The recruitment of immune cells to sites of injuryinvolves the concerted interactions of a large number of solublemediators. Several cytokines appear to play key roles in theseprocesses, particularly IL-1 and TNF. Both cytokines are derived frommononuclear cells and macrophages, along with other cell types.Physiologically, they produce many of the same proinflammatoryresponses, including fever, sleep and anorexia, mobilization andactivation of polymorphonuclear leukocytes, induction of cyclooxygenaseand lipoxygenase enzymes, increase in adhesion molecule expression,activation of B-cells, T-cells and natural killer cells, and stimulationof production of other cytokines. Other actions include a contributionto the tissue degeneration seen in chronic inflammatory conditions, suchas stimulation of fibroblast proliferation, induction of collagenase,etc. They have also been implicated in the process of bone resorptionand adipose tissue regulation. Thus, these cytokines play key roles in alarge number of pathological conditions, including rheumatoid arthritis,septic shock, inflammatory bowel disease, bone mass loss, cancer, dermalsensitization disorders, diabetes, obesity and neurological conditionssuch as ischemic stroke, closed-head injuries, etc.

Cytokines trigger a variety of changes in gene expression in theirtarget cells by binding and activating their respective cognatereceptors. Receptor activation sets in motion certain biochemicalevents, including the activation of otherwise latent transcriptionfactors. Members of the NF-κB Rel family of transcription factorsrepresent some of the most prominent of these transcription factors,having been implicated in the regulation of genes involved ininflammation, cell proliferation, apoptosis, and several other basiccellular functions (Verma et al. Genes Dev. 9, 2723 (1995); Baichwal &Baeuerle, Curr. Biol. 7, 94 (1997)).

The best studied member of this family of transcription factors isNF-κB, which generally exists in cells as a heterodimer of two proteins:p50 (NF-κB1) and p65 (Re1A), although homodimers of these individualcomponents are also possible (Baeuerle and Baltimore, Cell, 53, 211(1988); Baeuerle and Henkel, Annu. Rev. Immunol. 12, 141 (1994)). NF-κB,in its inactive form, resides in the cytoplasm of cells. In response tovarious types of stimuli, such as proinflammatory cytokines (e.g., TNFand IL-1), ultraviolet irradiation and viral infection (Verma, 1995;Baichwal, 1997; Cao et al. Science, 271, 1128 (1996)) NF-κB migrates tothe nucleus.

In its inactive state, the NF-κB heterodimer is held in the cytoplasm byassociation with inhibitory IκB proteins. Recently, thethree-dimensional structure of a NF-κB/IκB ternary complex has beensolved (Huxford et al. Cell, 95, 759 (1998); Jacobs et al. Cell, 95, 749(1998)). When cells are treated with the appropriate stimuli, such asIL-1 or TNF, intracellular signal transduction pathways are activatedthat lead to the eventual phosphorylation of IκB proteins on twospecific residues (serines 32 and 36 in IκBα, serines 19 and 23 inIκBβ). Mutation of one or both serine residues renders IκB resistant tocytokine-induced phosphorylation. This signal-induced phosphorylationtargets IκB for ubiquitination and proteosome-mediated degradation,allowing nuclear translocation of NF-κB (Thanos and Maniatis, Cell, 80,529 (1995)). The only regulated step in the IκB degradation pathway isthe phosphorylation of IκB by IkB kinases (IKK) (Yaron et al. EMBO J.16, 6486 (1997)).

Several intermediate steps in the TNF- and IL-1-activated signalingpathways that result in IκB phosphorylation have been elucidated inrecent years. Both pathways appear to merge at the level of the proteinkinase NIK (NF-κB-inducing kinase) (Malinin et al. Nature, 385, 540(1997); Song et al. Proc. Natl. Acad. Sci. USA, 94, 9792 (1997)).Similarly, the protein kinases MEKK1 and MLK3 have been implicated inthe induction of IKK activity (Lee et al. Proc. Natl. Acad. Sci. USA.95, 9319 (1998); Hehner et al. Mol. Cell. Biol. 20, 2556 (2000)). Whilethe specific details remain somewhat unclear regarding how these orother intermediate proteins may interact with and/or stimulate IKKactivity in cells, significant progress has been made in elucidating theenzymes responsible for IkB phosphorylation.

Two IKK enzymes, generally referred to as IKKα (or IKK-1) and IKK β (orIKK-2) (Woronicz et al. Science, 278, 866 (1997); Zandi et al. Cell, 91,243 (1997); Mercurio et al. Science, 278, 860 (1997)) have beendiscovered. Both forms of IKK can exist as homodimers and as IKKα/IKK βheterodimers. Another recently discovered component of the IκB kinasecomplex is a regulatory protein, known as IKK-gamma or NEMO(NF-κB-Essential Modulator) (Rothwarf et al. Nature, 395, 297 (1998)).NEMO does not contain a catalytic domain, and thus it appears to have nodirect kinase activity and it probably serves a regulatory function.Existing data suggest that the predominant form of IKK in cells is anIKKα/IKK β heterodimer associated with either a dimer or a trimer ofNEMO (Rothwarf et al. Nature 395, 297 (1998)).

Biochemical and molecular biology experiments have clearly identifiedIKKα and IKKβ, as the most likely mediators of TNF- and IL-1-induced IκBphosphorylation and degradation, which results in NF-κB activation andupregulation of families of genes involved in inflammatory processes(Woronicz et al. Science (1997); Karin, Oncogene 18, 6867 (1999); Karin,J. Biol. Chem. 274, 27339 (1999)). These kinases have also beenidentified as components of CD40 ligand-induced signaling. IKKα and IKKβhave very similar primary structures, displaying more than 50% overallsequence identity. In the kinase domain, their sequences are 65%identical.

Based on our present understanding of the critical role played by TNFand IL-1 in the wide array of pathological conditions described above,and the involvement of IKKα and IKKβ in the signal transduction of bothcytokines, the discovery of small molecules that potently andselectively inhibit either of these kinases would result in a majoradvancement in the therapy of those conditions. In this application wedescribe novel compounds which display such desirable activity.

BRIEF SUMMARY OF THE INVENTION

The present invention provides compounds useful in the treatment orprevention of inflammatory, metabolic, infectious or cell proliferativediseases or conditions, having the formula (I):

wherein

W is a 5-6, 6-6 or 5-5 or fused bicyclic ring system, wherein one orboth rings are aromatic, containing a nitrogen atom and from 0 to 3additional heteroatoms selected from the group consisting of N, O and S,wherein

-   -   (i) the ring fusion atoms are independently CH or N, with the        proviso that the ring fusion atoms are not both N; and    -   (ii) the atoms to which L, R¹ and R² are attached are        independently selected from the group consisting of ═C—, —CH—        and —N—;

R¹ is selected from the group consisting of —C(O)NR^(1a)R^(1b),—C(O)R^(1a), —CH(═NOH), —N(R^(1b))C(O)R^(1a), —SO₂NR^(1a)R^(1b),—SO₂R^(1a), —C(O)N(R^(1a))OR^(1b), —(C₁-C₄)alkylene-N(R^(1b))C(O)R^(1a),—(C₁-C₄)alkylene-C(O)NR^(1a)R^(1b) and heteroaryl; wherein R^(1a) andR^(1b) are selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl,(C₂-C₆)heteroalkyl, hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl,cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl; and optionally, R^(1a) is attachedto an adjacent ring member of W relative to the point of attachment ofR¹ to form an additional 5- or 6-membered fused ring, or R^(1a) andR^(1b) are combined with their intervening atoms to form a 3-, 4-, 5- or6-membered ring.

R² is selected from the group consisting of —NR^(2a)R^(2b) and —OH;wherein R^(2a) and R^(2b) are selected from hydrogen, (C₁-C₆)alkyl,(C₂-C₄)alkenyl, (C₂-C₆)heteroalkyl, hydroxy(C₁-C₄)alkyl,fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkoxy, —C(O)-heterocyclo(C₃-C₈)alkyl andC(O)-fluoro(C₁-C₄)alkyl; and optionally, R^(2a) and R^(2b) may becombined with the nitrogen atom to which each is attached to form a 5-,6- or 7-membered ring containing from 1-3 heteroatoms selected from N, Oand S.

L is a divalent linkage selected from the group consisting of a singlebond, (C₁-C₄)alkylene, —C(O)—, —C(O)N(R³)—, —SO₂N(R³)—, —C(R³)═C(R⁴)—,—O—, —S— and —N(R³)—; wherein R³ and R⁴ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl.

Q is selected from the group consisting of (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halogen, aryl, aryl(C₁-C₄)alkyl,heteroaryl, cyclo(C₃-C₈)alkyl, cyclo(C₅-C₈)alkenyl andheterocyclo(C₃-C₈)alkyl; each of which is optionally substituted asindicated below.

Within the above compounds of formula I, the compound is other than

The invention also provides compounds useful in the treatment orprevention of inflammatory, metabolic, infectious or cell proliferativediseases or conditions, having a formula selected from the groupconsisting of:

wherein

R¹ is selected from the group consisting of —C(O)NR^(1a)R^(1b),—C(O)R^(1b), —CH(═NOH), —N(R^(1b))C(O)R^(1a), —SO₂NR^(1a)R^(1b),—SO₂R^(1a), —C(O)N(R^(1a))OR^(1b), —(C₁-C₄)alkylene-N(R^(1b))C(O)R^(1a),—(C₁-C₄)alkylene-C(O)NR^(1a)R^(1b) and heteroaryl; wherein R^(1a) andR^(1b) are selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl,(C₂-C₆)heteroalkyl, hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl,cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl; and optionally, R^(1a) is attachedto an adjacent ring member of W relative to the point of attachment ofR¹ to form an additional 5- or 6-membered fused ring, or R^(1a) andR^(1b) are combined with their intervening atoms to form a 3-, 4-, 5- or6-membered ring.

L is a divalent linkage selected from the group consisting of a singlebond, (C₁-C₄)alkylene, —C(O)—, —C(O)N(R³)—, —SO₂N(R³)—, —C(R³)═C(R⁴)—,—O—, —S— and —N(R³)—; wherein R³ and R⁴ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl.

Q is selected from the group consisting of (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halogen, aryl, aryl(C₁-C₄)alkyl,heteroaryl, cyclo(C₃-C₈)alkyl, cyclo(C₅-C₈)alkenyl andheterocyclo(C₃-C₈)alkyl; each of which is optionally substituted asindicated below.

A¹ and A² are independently selected from the group consisting of ═C—,—CH— and —N—;

B¹ and B² are independently selected from the group consisting of═C(R^(5a))—, —C(R⁵)(R⁶)—, —C(O)—, ═N—, —N(R⁵)—, —O— and —S(O)_(m)—;

D¹ is selected from the group consisting of —C(R⁷)(R⁸)—, —N(R⁷)— and—O—;

D² is selected from the group consisting of —C(R⁹)(R¹⁰)—, —C(O)—,—N(R⁹)—, —O— and —S(O)_(n)—;

optionally, D¹-D² may be —(R¹¹)═C(OR¹²)— or —C(R¹¹)═N—;

Z¹ and Z² are independently CH or N;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl;

R^(5a), in each instance is independently selected from the groupconsisting of hydrogen, halogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl;

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen and (C₁-C₆)alkyl, aryl and aryl(C₁-C₄)alkyl.

The subscripts m and n are independently an integer of from 0 to 2; withthe proviso that D¹ and D² are not both —N(R⁹)— or —O—.

Unless otherwise indicated, the compounds provided in the above formulaare meant to include pharmaceutically acceptable salts, hydrates,solvates and prodrugs thereof.

In another aspect, the present invention provides pharmaceuticalcompositions comprising one or more compounds of the invention andpharmaceutically acceptable carrier, excipient or diluent.carrier orexcipient.

In yet another aspect, provides methods for the treatment or preventionof an inflammatory, metabolic, infectious or cell proliferative diseaseor condition, comprising administering to a subject in need thereof acompound of the invention.

Other objects, features and advantages of the present invention willbecome apparent to those skilled in the art from the followingdescription and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-7 provides structures for selected compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwisedefined.

The term “therapeutically effective amount” refers to the amount of thesubject compound that will elicit the biological or medical response ofa tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician. The term“therapeutically effective amount” includes that amount of a compoundthat, when administered, is sufficient to prevent development of, oralleviate to some extent, one or more of the symptoms of the conditionor disorder being treated. The therapeutically effective amount willvary depending on the compound, the disease and its severity and theage, weight, etc., of the mammal to be treated.

As used herein, the term “obesity” refers to the excessive accumulationof body fat. Obesity may have genetic, environmental (e.g., expendingless energy than is consumed) and regulatory determinants. Obesityincludes exogenous, hyperinsulinar, hyperplasmic, hypothyroid,hypothalamic, symptomatic, infantile, upper body, alimentary,hypogonadal, simple and central obesity, hypophyseal adiposity andhyperphagia. Cardiovascular disorders, such as hypertension and coronaryartery disease, and metabolic disorders, such as hyperlidemia anddiabetes, are commonly associated with obesity.

As used herein, “diabetes” refers to type I diabetes mellitus (juvenileonset diabetes, insulin dependent-diabetes mellitus or IDDM) or type Hdiabetes mellitus (non-insulin-dependent diabetes mellitus or NIDDM),preferably, NIDDM.

As used herein, “syndrome X” refers to a collection of abnormalitiesincluding hyperinsulinemia, obesity, elevated levels of triglycerides,uric acid, fibrinogen, small dense LDL particles and plasminogenactivator inhibitor 1 (PAI-1), and decreased levels of HDL cholesterol.Syndrome X is further meant to include metabolic syndrome.

As used herein, the term “eating disorder” refers to an emotional and/orbehavioral disturbance associated with an excessive decrease in bodyweight and/or inappropriate efforts to avoid weight gain, e.g., fasting,self-induced vomiting, laxative or diuretic abuse. Exemplary eatingdisorders include anorexia nervosa and bulimia.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The terms “signal transduction”, “signaling” and related terms refer toa process whereby an extracellular signal (e.g, the concentration of acytokine, hormone, neurotransmitter, growth factor) is transmitted via acascade of intracellular protein-protein interactions and generates oneor more cellular responses (e.g., gene transcription, protein secretion,mitosis, apoptosis). The interaction of an extracellular signalingmolecule (e.g, a cytokine, a hormone, a neurotransmitter, a growthfactor) with one or more transmembrane protein receptors at the cellsurface can activate one or more signal transduction pathways. Theprotein-protein interactions in a signal transduction pathway may bemultivalent and include covalent and/or non-covalent proteinmodification. An intracellular signaling molecule, i.e., a signaltransducing protein or a signal transducer, may be involved in one ormore signal transduction pathways. As described herein, protein-proteininteractions includes direct and indirect interactions.

As used herein, the term “IKK” refers to an I-κB kinase protein orvariant thereof that is capable of mediating a cellular response to IL-1in vitro or in vivo. IKK may be capable of transphosphorylation of otherproteins or autophosphorylation. In preferred embodiments, IKK is IKKβand/or IKKα.

IKK variants include proteins substantially homologous to native IKK,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., IKKderivatives, homologs and fragments). The amino acid sequence of an IKKvariant preferably is at least about 80% identical to a native IKK, morepreferably at least about 90% identical, and most preferably at leastabout 95% identical.

As used herein, the term “IRAK” refers to an interleukin-1 (IL-1)receptor-associated kinase protein or variant thereof that is capable ofmediating a cellular response to IL-1 in vitro or in vivo. IRAK may bekinase-active or kinase-inactive. Exemplary kinase active IRAKs includeIRAK-1 and IRAK-4. Exemplary kinase inactive IRAKs include IRAK-2 andIRAK-3 (also known as IRAK-M). Kinase-active IRAKs may be capable oftransphosphorylation of other proteins or autophosphorylation. Inpreferred embodiments, IRAK is IRAK-1 and/or IRAK-4.

IRAK variants include proteins substantially homologous to native IRAK,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., IRAKderivatives, homologs and fragments). The amino acid sequence of an IRAKvariant preferably is at least about 80% identical to a native IRAK,more preferably at least about 90% identical, and most preferably atleast about 95% identical.

“Acyl” or “alkanoyl” means the group C(O)R′, where R′ is hydrogen,alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, and variations ofthese groups in which one or more carbon atoms have been replaced withheteroatoms.

“Alkyl” means a linear saturated monovalent hydrocarbon radical or abranched saturated monovalent hydrocarbon radical having the number ofcarbon atoms indicated in the prefix. For example, (C₁-C₆)alkyl is meantto include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, andthe like. For each of the definitions herein (e.g., alkyl, alkenyl,alkoxy, arylalkyloxy), when a prefix is not included to indicate thenumber of main chain carbon atoms in an alkyl portion, the radical orportion thereof will have six or fewer main chain carbon atoms.

“Alkylene” means a linear saturated divalent hydrocarbon radical or abranched saturated divalent hydrocarbon radical having the number ofcarbon atoms indicated in the prefix. For example, (C₁-C₆)alkylene ismeant to include methylene, ethylene, propylene, 2-methylpropylene,pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical or a branchedmonovalent hydrocarbon radical having the number of carbon atomsindicated in the prefix and containing at least one double bond. Forexample, (C₂-C₆)alkenyl is meant to include, ethenyl, propenyl, and thelike.

“Alkynyl” means a linear monovalent hydrocarbon radical or a branchedmonovalent hydrocarbon radical containing at least one triple bond andhaving the number of carbon atoms indicated in the prefix. For example,(C₂-C₆)alkynyl is meant to include ethynyl, propynyl, and the like.

“Alkoxy”, “aryloxy”, “arylalkyloxy”, “heteroalkyloxy” or“heteroarylalkyloxy” means a radical —OR where R is an alkyl, aryl,arylalkyl, heteroalkyl or heteroarylalkyl respectively, as definedherein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, andthe like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms which is substituted independently withone to four substituents, preferably one, two, or three substituentsselected from, for example, alkyl, cycloalkyl, cycloalkyl-alkyl, halo,nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino,dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, COR (where R ishydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl),—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl), —CR′R″)_(n)—CONR^(a)R^(b)(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R^(a) and R^(b) are, independently of each other,hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, phenyl orphenylalkyl), or —NR″C(O)R′, —NR″CO₂R′, —NR′C(O)NR″R′″, —SO₂R′,—SO₂NR′R″ or —OC(O)NR′R″ (where R′, R″ and R″′are independentlyhydrogen, alkyl, cycloalkyl, aryl, arylalkyl, —C(O)-alkyl, —CO₂-alkyl,—C(O)-heterocycloalkyl, —C(O)-fluoroalkyl, and heteroaryl). Optionally,two groups R′, R″, R′″, R^(a) or R^(b) attached to a common nitrogenatom can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring having from 1-3 heteroatoms selected from N, O and S.Two of the substituents on adjacent atoms of the aryl ring mayoptionally be replaced with a substituent of the formula-T—C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl, ring may optionallybe replaced with a substituent of the formula -A-(CH₂)_(r)—B-, wherein Aand B are independently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—,—S(O)₂NR′— or a single bond, and r is an integer of from 1 to 3. One ofthe single bonds of the new ring so formed may optionally be replacedwith a double bond. Alternatively, two of the substituents on adjacentatoms of the aryl ring may optionally be replaced with a substituent ofthe formula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— is selected fromhydrogen or unsubstituted (C₁-C₆)alkyl. More specifically the term arylincludes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and2-naphthyl, and the substituted derivatives thereof.

“Arylalkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylene group(having six or fewer main chain carbon atoms) and R^(b) is an aryl groupas defined herein, e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like.

“Arylheteroalkyl” means a radical —R^(a)R^(b) where R^(a) is anheteroalkylene group and R^(b) is an aryl group as defined herein, e.g.,2-hydroxy-2-phenyl-ethyl, 2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl, andthe like.

“Cycloalkyl” means a saturated monovalent cyclic hydrocarbon radical ofthree to seven ring carbons. The cycloalkyl may be optionallysubstituted independently with one, two, or three substituents selectedfrom alkyl, optionally substituted phenyl, or —C(O)R (where R ishydrogen, alkyl, haloalkyl, amino, acylamino, monoalkylamino,dialkylamino, hydroxy, alkoxy, or optionally substituted phenyl). Morespecifically, the term cycloalkyl includes, for example, cyclopropyl,cyclohexyl, phenylcyclohexyl, 4-carboxycyclohexyl,2-carboxamidocyclohexyl, 2-dimethylaminocarbonyl-cyclohexyl, and thelike.

“Cycloalkyl-alkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a cycloalkyl group as defined herein, e.g.,cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, andthe like.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like, andfurther includes those alkyl groups such as perfluoroalkyl in which allhydrogen atoms are replaced by fluorine atoms. The prefix “halo” and theterm “halogen” when used to describe a substituent, refer to —F, —Cl,—Br and —I. The term “fluoroalkyl” means alkyl substituted with one ormore same or different fluorine atoms, e.g., —CF₃ and —CH₂CF₃.

“Heteroalkyl” means an alkyl radical as defined herein with one, two orthree substituents independently selected from cyano, —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom of the heteroalkyl radical. R^(a) ishydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl,alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- ordialkylcarbamoyl. R^(b) is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, aryl or arylalkyl. R^(c) is hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkoxycarbonyl,aryloxycarbonyl, carboxamido, mono- or dialkylcarbamoyl oralkylsulfonyl. R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, amino, monoalkylamino,dialkylamino, or hydroxyalkyl. Representative examples include, forexample, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl,benzyloxymethyl, 2-cyanoethyl, and 2-methylsulfonyl-ethyl. For each ofthe above, R^(a), R^(b), R^(c), and R^(d) can be further substituted byNH₂, fluorine, alkylamino, dialkylamino, OH or alkoxy. Additionally, theprefix indicating the number of carbon atoms (e.g., C₁-C₁₀) refers tothe total number of carbon atoms in the portion of the heteroalkyl groupexclusive of the cyano, —OR^(a), —NR^(b)R^(c), or —S(O)_(n)R^(d)portions.

“Heteroaryl” means a monovalent monocyclic or bicyclic radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring isoptionally substituted independently with one to four substituents,preferably one or two substituents, selected from alkyl, cycloalkyl,cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino,monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR(where R is hydrogen, alkyl, phenyl or phenylalkyl, —(CR′R″)_(n)—COOR(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenylor phenylalkyl), or —CR′R″)_(n)—CONR^(a)R^(b) (where n is an integerfrom 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a)and R^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, heteroalkyl, phenyl or phenylalkyl). More specificallythe term heteroaryl includes, but is not limited to, pyridyl, furanyl,thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, imidazolyl,oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl,benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl,benzoxazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, benzimidazolyl,benzisoxazolyl, benzothienyl, and the derivatives thereof.

“Heteroarylalkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a heteroaryl group as defined herein, e.g.,pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

“Heterocyclyl” or “cycloheteroalkyl” means a saturated or unsaturatednon-aromatic cyclic radical of 3 to 8 ring atoms in which one or tworing atoms are heteroatoms selected from O, NR (where R is independentlyhydrogen or alkyl) or S(O)_(n) (where n is an integer from 0 to 2), theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl group. The heterocyclyl ring may be optionallysubstituted independently with one, two, or three substituents selectedfrom alkyl, cycloalkyl, cycloalkyl-alkyl, halo, nitro, cyano, oxo,hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, haloalkyl,haloalkoxy, —COR (where R is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—COOR (n is aninteger from 0 to 5, R′ and R″ are independently hydrogen or alkyl, andR is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl orphenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from0 to 5, R′ and R″ are independently hydrogen or alkyl, R^(a) and R^(b)are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl). More specifically the termheterocyclyl includes, but is not limited to, tetrahydropyranyl,piperidino, N- methylpiperidin-3-yl, piperazino,N-methylpyrrolidin-3-yl, 3-pyrrolidino, 2-pyrrolidon-1-yl, morpholino,thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,pyrrolidinyl, and the derivatives thereof. The prefix indicating thenumber of carbon atoms (e.g., C₃-C₁₀) refers to the total number of ringatoms, whether carbon or heteroatoms in the cycloheteroalkyl orheterocyclyl group.

“Heterocyclylalkyl”, “cycloheteroalkyl-alkyl” or“heterocycloalkyl-alkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heterocyclyl group as defined herein,e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl,3-piperidinylmethyl, and the like.

“Hydroxyalkyl” means an alkyl radical as defined herein, substitutedwith one or more, preferably one, two or three hydroxy groups, providedthat the same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxymethyl-2-methylpropyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,1-hydroxymethyl-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyland 2-hydroxymethyl-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-hydroxymethyl-2-hydroxyethyl. Accordingly, asused herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

“Optionally substituted phenyl” means a phenyl ring which is optionallysubstituted independently with one to four substituents, preferably oneor two substituents generally selected from the substituents providedfor aryl groups above. More particularly, the substituents can beselected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,arylalkyl, halo, nitro, cyano, cyanoalkyl, hydroxy, hydroxyalkyl,alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl (e.g.,fluoroalkyl), haloalkoxy (e.g, fluoroalkoxy), heteroalkyl,heteroalkenyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl,—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—CONR^(a)R^(b)(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R^(a) and R^(b) are, independently of each other,hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or—NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′C(O)NR″R′″, —SO₂R′, —SO₂NR′R″,—(C₁-C₄)alkylene-SO₂R′, —C₁-C₄)alkylene-SO₂NR′R″ and —OC(O)NR′R″ (whereR′, R″ and R′″ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, —C(O)-alkyl, —CO₂-alkyl, —C(O)-heterocycloalkyl,—C(O)-fluoroalkyl, and heteroaryl). Optionally, two groups R′, R″, R′″,R^(a) or R^(b) attached to a common nitrogen atom can be combined withthe nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring havingfrom 1-3 heteroatoms selected from N, O and S.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function and/or expression ofIKK, where IKK function may include kinase activity and/orprotein-binding. Modulation may occur in vitro or in vivo. Modulation,as described herein, includes the inhibition or activation of IKKfunction and/or the downregulation or upregulation of IKK expression,either directly or indirectly. A modulator preferably activates IKKfunction and/or upregulates IKK expression. More preferably, a modulatoractivates or inhibits IKK function and/or upregulates or downregulatesIKK expression. Most preferably, a modulator inhibits IKK functionand/or downregulates IKK expression. The ability of a compound toinhibit IKK function can be demonstrated in an enzymatic assay or acell-based assay (e.g., inhibition of IL-1-stimulated NF-κB activation).

“Pharmaceutically acceptable carrier or excipient” means a carrier orexcipient that is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or excipient that is acceptable forveterinary use as well as human pharmaceutical use. A “pharmaceuticallyacceptable carrier or excipient” as used in the specification and claimsincludes both one and more than one such carrier or excipient.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

(1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,trimethylamine, N-methylglucamine, and the like.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For Example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.A wide variety of prodrug derivatives are known in the art, such asthose that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound of the present invention which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound of the invention.

“Treating” or “treatment of” a disease includes inhibiting the disease,e.g., arresting or reducing the development of the disease or itsclinical symptoms, or relieving the disease, e.g., causing regression ofthe disease or its clinical symptoms.

“Preventing” or “prevention of” the disease includes, e.g. causing theclinical symptoms of the disease not to develop in a mammal that may beexposed to or predisposed to the disease but does not yet experience ordisplay symptoms of the disease.

As used herein, the term “condition or disorder responsive to IKKmodulation” refers to a condition or disorder that is at least partiallyresponsive to or affected by IKK modulation (e.g., an IKK inhibitorresults in some improvement in patient well-being in at least somesubjects suffering from said condition or disorder).

As used herein, the term “IKK-mediated disease or condition” and relatedterms and phrases refer to a disease, disorder or conditioncharacterized by inappropriate, e.g., less than or greater than normal,IKK activity. Inappropriate IKK functional activity might arise as theresult of IKK expression in cells which normally do not express IKK,increased IKK expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased IKK expression. AnIKK-mediated disease or condition may be completely or partiallymediated by inappropriate IKK functional activity. However, anIKK-mediated disease or condition is one in which modulation of IKKresults in some effect on the underlying disease or condition (e.g., anIKK inhibitor results in some improvement in patient well-being in atleast some patients).

“Optional” or “optionally” in the above definitions means that thesubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “heterocyclogroup optionally mono- or di-substituted with an alkyl group” means thatthe alkyl may but need not be present, and the description includessituations where the heterocyclo group is mono- or disubstituted with analkyl group and situations where the heterocyclo group is notsubstituted with the alkyl group.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may exist in stereoisomeric form if theypossess one or more asymmetric centers or a double bond with asymmetricsubstitution and, therefore, can be produced as individual stereoisomersor as mixtures. Unless otherwise indicated, the description is intendedto include individual stereoisomers as well as mixtures. The methods forthe determination of stereochemistry and the separation of stereoisomersare well-known in the art (see discussion in Chapter 4 of AdvancedOrganic Chemistry, 4th edition J. March, John Wiley and Sons, New York,1992).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). Radiolabled compounds are useful astherapeutic agents (e.g., chemotherapeutic agents), research reagents(e.g., IKKβ binding assay reagents) and diagnostic agents (e.g., in vivoimaging agents). All isotopic variations of the compounds of theinvention, whether radioactive or not, are intended to be encompassedwithin the scope of the invention.

Embodiments of the Invention

A class of compounds that interact with IKK has been discovered.Depending on the biological environment (e.g., cell type, pathologicalcondition of the host, etc.), these compounds can activate or block theactions of IKK. By activating or inhibiting IKK, the compounds will finduse as therapeutic agents capable of modulating diseases or conditionsresponsive to IKK modulation and/or mediated by IKK. As noted above,examples of such diseases and disorders include rheumatoid arthritis,septic shock, inflammatory bowel disease, bone mass loss, cancer, dermalsensitization disorders, diabetes, obesity and neurological conditionssuch as ischemic stroke and closed-head injuries. Additionally, thecompounds are useful for the treatment of complications of thesediseases and disorders (e.g., diabetic neuropathy). While the compoundsof the invention are believed to exert their effects through modulationof IKK, the mechanism of action by which the compound act is not alimiting embodiment of the invention. For example, compounds of theinvention may interact with one or more IKK isotypes, e.g., IKKβ and/orIKKα. In still other embodiments, compounds of the invention maymodulate IRAK and/or IRAK and or one or more IKK isotypes. Accordingly,these compounds have further utility in the treatment of diseases orconditions mediated by IRAK.

Compounds contemplated by the invention include, but are not limited to,the exemplary compounds provided herein.

Compounds

In one aspect, the present invention provides compounds useful in thetreatment of inflammatory, metabolic, infectious or cell proliferativediseases or conditions, having the formula (I):

In formula I, W is a 5-6, 6-6 or 5-5 or fused bicyclic ring system,wherein one or both rings are aromatic, containing a nitrogen atom andfrom 0 to 3 additional heteroatoms selected from the group consisting ofN, O and S, wherein

-   -   (iii) the ring fusion atoms are independently CH or N, with the        proviso that the ring fusion atoms are not both N; and    -   (iv) the atoms to which L, R¹ and R² are attached are        independently selected from the group consisting of ═C—, —CH—        and —N—.

R¹ is selected from the group consisting of —C(O)NR^(1a)R^(1b),—C(O)R^(1a), —CH(═NOH), —N(R^(1b))C(O)R^(1a), —SO₂NR^(1a)R^(1b),—SO₂R^(1a), —C(O)N(R^(1a))OR^(1b), —(C₁-C₄)alkylene-N(R^(1b))C(O)R^(1a),—(C₁-C₄)alkylene-C(O)NR^(1a)R^(1b) and heteroaryl; wherein R^(1a) andR^(1b) are selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl,(C₂-C₆)heteroalkyl, hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl,cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-C₁-C₄)alkyl; and optionally, R^(1a) is attachedto an adjacent ring member of W relative to the point of attachment ofR¹ to form an additional 5- or 6-membered fused ring, or R^(1a) andR^(1b) are combined with their intervening atoms to form a 3-, 4-, 5- or6-membered ring. In one embodiment, R¹ is selected from —C(O)NR²R^(1b),—SO₂NR^(1a)R^(1b), —SO₂R^(1a), —C(O)R^(1a), imidazolyl, pyrazolyl,tetrazolyl, oxazolyl, thiazolyl, thienyl and pyridyl. In anotherembodiment, R¹ is selected from —C(O)NHR^(1a), —O₂NHR^(1a), —SO₂R^(1a),—C(O)CH₃ and thiazolyl. In another embodiment, R¹ is selected from—C(O)NHR^(1a), —SO₂NHR^(1a) and —C(O)CH₃. In still another embodiment,R¹ is —(O)NH₂.

R² is selected from the group consisting of —NR^(2a)R^(2b) and —OH;wherein R^(2a) and R^(2b) are selected from hydrogen, (C₁-C₆)alkyl,(C₂-C₄)alkenyl, (C₂-C₆)heteroalkyl, mono- or di-hydroxy(C₁-C₄)alkyl,fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkoxy, —C(O)-heterocyclo(C₃-C₈)alkyl andC(O)-fluoro(C₁-C₄)alkyl; and optionally, R^(2a) and R^(2b) may becombined with the nitrogen atom to which each is attached to form a 5-,6- or 7-membered ring containing from 1-3 heteroatoms selected from N, Oand S. In one embodiment, R² is —NHR^(2b). In another embodiment, R² is—NH₂. In still other embodiments, R² is —NR^(2a)R^(2b) wherein R^(2a)and R^(2b), taken together with the nitrogen to which each is attached,form a 5- or 6-membered ring having from 1-3 heteroatom ring members,and which is further substituted with from one to three substituentsselected from OH, CONH₂ and NH₂.

L is a divalent linkage selected from the group consisting of a singlebond, (C₁-C₄)alkylene, —C(O)—, —C(O)N(R³)—, —SO₂N(R³)—, —C(R³)═C(R⁴)—,—O—, —S— and —N(R³)—; wherein R³ and R⁴ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl. In onegroup of embodiments, L is selected from a single bond, (C₁-C₄)alkyl and—C(O)—.

Q is selected from the group consisting of (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halogen, aryl, aryl(C₁-C₄)alkyl,heteroaryl, cyclo(C₃-C₈)alkyl, cyclo(C₅-C₈)alkenyl andheterocyclo(C₃-C₈)alkyl, wherein each of the moieties is optionallyfurther substituted as indicated below. In one embodiment, Q is selectedfrom the group consisting of phenyl, naphthyl, pyridyl, furyl, thienyl,thiazolyl, isothiazolyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl,pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidyl,benzofuryl, tetrahydrobenzofuryl, isobenzofuryl, benzthiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolyl, tetrahydroquinolyl, isoquinolyl, benzimidazolyl,benzisoxazolyl, benzothienyl, cyclopentyl and cyclohexyl, each of whichis substituted or unsubstituted. In another embodiment, Q isun(substituted) phenyl, un(substituted) thienyl, orun(substituted)(C₂-C₆)alkynyl wherein from 1 to 3 substituents may bepresent and are selected from halogen, cyano, nitro,cyano(C₂-C₆)alkenyl, nitro(C₂-C₆)alkenyl, —R′, —OR′, —NR′R″, —C(O)′,—CO₂R′, —C(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′C(O)NR″R′″, —S(O)R′,—SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —OC(O)NR′R″, —X—C(O)R′, —X—CO₂R′,—X—C(O)NR′R″, —X—NR″C(O)R′, —X—NR″CO₂R′, —X—NR′C(O)NR″R′″, —X—S(O)R′,—X—SO₂R′, —X—SO₂NR′R″, —X—NR″SO₂R′ and —X—OC(O)NR′R″, and optionally R′or R″ is attached to an adjacent ring atom on the phenyl group orthienyl group to form a 5- or 6-membered fused ring.

X is (C₁-C₆)alkylene. Preferably a methylene, ethylene or propylene.

R′, R″ and R′″ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl, (C₁-C₆)heteroalkyl,hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl,cyano(C₁-C₄)haloalkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkoxy, —C(O)-heterocyclo(C₃-C₈)alkyl and—C(O)-fluoro(C₁-C₄)alkyl. Optionally, any two of R′, R″ and R′″ can becombined with their intervening atom(s) to form a 5-, 6- or 7-memberedring containing from 1-3 heteroatoms selected from N, O and S.

Within the above compounds of formula I, the compound is other than

Within these embodiments are several groups of preferred embodiments,described below. In each of these preferred embodiments, the compound isother than

One group of preferred embodiments is represented by the formula:

wherein

X¹, X² and X³ are independently selected from the group consisting of═C—, —CH— and —N—;

Y¹, Y², Y³ and Y⁴ are independently selected from the group consistingof ═C(R^(5a))—, —C(R⁵)(R⁶)—, —C(O)—, ═N—, —N(R⁵)—, —O— and —S(O)_(m)—;

Z¹ and Z² are independently CH or N;

Each R⁵ and R⁶ is independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl,hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl, heteroaryl,heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl;

Each R^(5a) is independently selected from the group consisting ofhydrogen, halogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl;

the subscript m is an integer of from 0 to 2; and

R¹, R², L and Q have the meanings and preferred groupings providedabove.

Another group of preferred embodiments is represented by the formula:

wherein

Y⁵ is independently selected from the group consisting of ═C(R′″),—C(R⁵)(R⁶)—, —C(O)—, ═N—, —N(R⁵)—, —O— and —S(O)_(m) and R¹, R², L, Q,X¹, X², X³, Y¹, Y², Y³, Y⁴, Z¹, Z², R⁵, R^(5a), R⁶ and the subscript mhave the meanings and preferred groupings provided above.

Another group of preferred embodiments is represented by the formula:

wherein R¹, R², L, Q, X¹, X², X³, Y¹, Y², Y³ Z¹, Z², R⁵, R^(5a), R⁶ andthe subscript m have the meanings and preferred groupings providedabove.

Preferred are those embodiments that combine preferred groups.Accordingly, in one group of preferred embodiments, R¹ is selected from<(O)NR^(1a)R^(1b), —SO₂NR^(1a)R^(1b), —SO₂R^(1a), —C(O)R^(1a),imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl, thienyl andpyridyl, and R² is —NHR^(2b). In another group of preferred embodiments,R¹ is selected from —C(O)NHR^(1a), —SO₂NHR^(1a), —SO₂R^(1a), —C(O)CH₃and thiazolyl, and R² is —NHR^(2b). In yet another group of preferredembodiments, R¹ is selected from C(O)NHR^(1a), —SO₂NHR^(1a) and—C(O)CH₃, and R² is —NHR^(2b). In still another group of preferredembodiments, R¹ is —C(O)NHR^(1a) and R² is —NHR^(2b). In still furtherpreferred embodiments, R¹ is —(O)NH₂ and R² is —NH₂.

One group of preferred embodiments is represented by the formula (III):

In formula III, R¹, R², R^(5a), L, Q, X¹, X², Y³ and Y⁴ have themeanings and preferred groupings provided above. Preferably, R^(5a) ishydrogen or halogen, and is independent of any remaining R^(5a)substituents that are present as part of Y³ or Y⁴.

Another group of preferred embodiments is represented by the formula(IV):

R¹, R², L, Q, X¹, X³, Y³ and Y⁴ have the meanings and preferredgroupings provided above.

Another group of preferred embodiments is represented by the formula(V):

In formula V, R¹, R², R^(5a), L, Q, X³, Y¹ and Y² have the meanings andpreferred groupings provided above.

Still another group of preferred embodiments is represented by theformula (VI):

In formula VI, each R² is independently selected from hydrogen, halogen,(C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl,hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl, with preferredmembers being those that have been described above. R¹, R², L and Q havethe meanings and preferred groupings provided above. Preferably, R^(5a)attached to the six-membered ring is hydrogen. More preferably, eachR^(5a) is hydrogen.

In related, and preferred embodiments of formula VI, L is a bond; Q isphenyl, thienyl or (C₂-C₆)alkynyl, wherein any phenyl, thienyl oralkynyl portion is optionally substituted as indicated above in thegeneral discussion of Q; and the R^(5a) attached to the five-memberedring is (C₁-C₆)alkyl.

Still other preferred embodiments are provided are formulae A-G, below,wherein the phenyl and thienyl rings can be substituted orunsubstituted. Additionally, in formula G, the symbol R represents asubstituted or unsubstituted (C₁-C₄)alkyl. The remaining substituentshave the meanings provided above with respect to formula I, as well aspreferred embodiments as recited for formula I as well as formulae III,V and VI.

Exemplary compounds of the invention are provided in FIGS. 1-7.

The present invention also provides compounds useful in the treatment ofinflammatory, metabolic, infectious or cell proliferative diseases orconditions, having the formula:

wherein

R¹ is selected from the group consisting of —C(O)NR^(1a)R^(1b),—C(O)R^(1a), —CH(═NOH), —N(R^(1b))C(O)R^(1a), —SO₂NR^(1a)R^(1b),—SO₂R^(1a), —C(O)N(R^(1a))OR^(1b), —(C₁-C₄)alkylene-N(R^(1b))C(O)R^(1a),(C₁-C₄)alkylene-C(O)NR^(1a)R^(1b) and heteroaryl; wherein R^(1a) andR^(1b) are selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl,(C₂-C₆)heteroalkyl, hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl,cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl; and optionally, R^(1a) is attachedto an adjacent ring member of W relative to the point of attachment ofR¹ to form an additional 5- or 6-membered fused ring. In one embodiment,R¹ is selected from —C(O)NR^(1a)R^(1b), SO₂NR^(1a)R^(1b), —SO₂R^(1a),—C(O)R^(1a), imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl,thienyl and pyridyl. In another embodiment, R¹ is selected from—C(O)NHR^(1a), —SO₂NHR^(1a), —SO₂R^(1a), —(O)CH₃ and thiazolyl. Inanother embodiment, R¹ is selected from —(O)NHR^(1a), —SO₂NHR^(1a) and—C(O)CH₃. In still another embodiment, R¹ is —(O)NH₂

L is a divalent linkage selected from the group consisting of a singlebond, (C₁-C₄)alkylene, —C(O)—, —C(O)N(R³)—, —SO₂N(R³)—, —C(R³)═C(R⁴)—,—O—, —S— and —N(R³)—; wherein R³ and R⁴ are independently selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl. In onegroup of embodiments, L is selected from a single bond, (C₁-C₄)alkyl and—C(O)—.

Q is selected from the group consisting of (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halogen, aryl, aryl(C₁-C₄)alkyl,heteroaryl, cyclo(C₃-C₈)alkyl, cyclo(C₅-C₆)alkenyl andheterocyclo(C₃-C₈)alkyl, wherein each of the moieties is optionallyfurther substituted as indicated below. In one embodiment, Q is selectedfrom the group consisting of phenyl, naphthyl, pyridyl, furyl, thienyl,thiazolyl, isothiazolyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl,pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidyl,benzofuryl, tetrahydrobenzofuryl, isobenzofuryl, benzthiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolyl, tetrahydroquinolyl, isoquinolyl, benzimidazolyl,benzisoxazolyl, benzothienyl, cyclopentyl and cyclohexyl, each of whichis substituted or unsubstituted. In another embodiment, Q isun(substituted) phenyl, un(substituted) thienyl, orun(substituted)(C₂-C₆)alkynyl wherein from 1 to 3 substituents may bepresent and are selected from halogen, cyano, nitro,cyano(C₂-C₆)alkenyl, nitro(C₂-C₆)alkenyl, —R′, —OR′, —NR′R″, —C(O)R′,—CO₂R′, —C(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′C(O)NR″R′″, —S(O)R′,—SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —OC(O)NR′R″, —X—C(O)R′, —X—CO₂R′,—X—C(O)NR′R″, —X—NR″C(O)R′, —X—NR″CO₂R′, —X—NR′C(O)NR″R′″, —X—S(O)R′,—X—SO₂R′, —X—SO₂NR′R″, —X—NR″SO₂R′ and —X—OC(O)NR′R″, and optionally R′or R″ is attached to an adjacent ring atom on the phenyl group orthienyl group to form a 5- or 6-membered fused ring.

X is (C₁-C₆)alkylene. Preferably a methylene, ethylene or propylene.

R′, R″ and R′″ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl, (C₁-C₆)heteroalkyl,hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl,cyano(C₁-C₄)haloalkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkoxy, —C(O)-heterocyclo(C₃-C₈)alkyl and—C(O)-fluoro(C₁-C₄)alkyl. Optionally, any two of R′, R″ and R′″ can becombined with their intervening atom(s) to form a 5-, 6- or 7-memberedring containing from 1-3 heteroatoms selected from N, O and S.

A¹ and A² are independently selected from the group consisting of ═C—,—CH— and —N—;

B¹ and B² are independently selected from the group consisting of═C(R^(5a))—, —C(R⁵)(R⁶)—, —C(O)—, ═N—, —N(R⁵)—, — and —S(O)_(m)—;

D¹ is selected from the group consisting of —C(R⁷)(R⁸)—, —N(R⁷)— and—O—;

D² is selected from the group consisting of —C(R⁹)(R¹⁰)—, —C(O)—,—N(R⁹)—, —and —S(O)_(n)—;

optionally, D¹-D² may be —C(R¹¹)═C(OR¹²)— or —C(R¹¹)═N—,

Z¹ and Z² are independently CH or N;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl;

R^(5a) is independently selected from the group consisting of hydrogen,halogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl,hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl, heteroaryl,heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl;

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen and (C₁-C₆)alkyl, aryl and aryl(C₁-C₄)alkyl; and

the subscripts m and n are independently an integer of from 0 to 2; withthe proviso that D¹ and D² are not both —N(R⁹)— or —O—.

One group of preferred embodiments is represented by the formula:

wherein B³ and B⁴ are independently C(R^(5a)) or N. R¹, L, Q, D¹ and D²have the meanings and preferred groupings provided above.

In sum, the invention encompasses novel compounds, novel pharmaceuticalcompositions and/or novel methods of use. While some compounds disclosedherein may be available from commercial sources, the pharmaceuticalcompositions or methods of using these compounds are novel. Unlessotherwise indicated, it is to be understood that the invention includesthose compounds that are novel, as well as pharmaceutical compositions,various methods (e.g., methods of treating or preventing certainIKK-mediated diseases or conditions), and the like which include boththe novel compounds of the invention and compounds that are commerciallyavailable.

Compounds contemplated by the invention include, but are not limited to,the exemplary compounds provided herein.

Preparation of the Compounds

Exemplary methods for the preparation of the compounds of the inventionare provided below and in the Examples. One of skill in the art willunderstand that additional methods are also useful. In other words, thecompounds of the invention can be made using conventional organicsynthetic methods, starting materials, reagents and reactions known inthe art.

Alternatively, compounds such as ia above, can be prepared by themethods illustrated in Scheme 1c.

One of skill in the art will appreciate that the substituents on theheterobicyclic ring scaffold, e.g., Q-L, R¹ and R², can be alteredbefore, during or after preparation of the scaffold and that suitableadjustments in the exemplary conditions (e.g., temperatures, solvents,etc.) can be made. Additionally, one of skill in the art will recognizethat protecting groups (PG) may be necessary for the preparation ofcertain compounds and will be aware of those conditions compatible witha selected protecting group.

Compositions

In another aspect, the present invention provides pharmaceuticalcompositions comprising one or more compounds of the invention incombination with a pharmaceutically acceptable carrier, excipient ordiluent.

Pharmaceutically acceptable excipient such as sterile saline,methylcellulose solutions, detergent solutions or other medium, water,gelatin, oils, etc. The compounds or compositions may be administeredalone or in combination with any convenient carrier, diluent, etc., andsuch administration may be provided in single or multiple dosages. Thecompositions are sterile, particularly when used for parenteraldelivery. However, oral unit dosage formes need not be sterile. Usefulcarriers include water soluble and water insoluble solids, fatty acids,micelles, inverse micelles, liposomes and semi-solid or liquid media,including aqueous solutions and non-toxic organic solvents. All of theabove formulations may be treated with ultrasounds, stirred, mixed,high-shear mixed, heated, ground, milled, aerosolized, pulverized,lyophilized, etc., to form pharmaceutically acceptable compositions.

In another embodiment, the invention provides the subject compounds inthe form of a prodrug, which can be metabolically or chemicallyconverted to the subject compound by the recipient host. A wide varietyof prodrug derivatives are known in the art such as those that rely onhydrolytic cleavage or oxidative activation of the prodrug.

The compositions may be provided in any convenient form, includingtablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, suppositories, etc. As such, the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

Still other compositions of the present invention are those that combinetwo or more of the present compounds in one formulation, or one compoundfrom the present invention with a second antiinflammatory,antiproliferative or antidiabetic agent.

Methods of Use

In yet another aspect, the present invention provides methods oftreating or preventing a disease or condition associated withinflammation, a metabolic disorder, infection, cancer or an immunedisease or condition by administering to a subject having such acondition or disease, a therapeutically effective amount of a compoundor composition of the invention.

In one group of embodiments, diseases or conditions, including chronicdiseases, of humans or other species can be treated or prevented withinhibitors of IKK function and/or inhibitors of IRAK function. Thesediseases or conditions include (1) inflammatory or allergic diseasessuch as systemic anaphylaxis and hypersensitivity responses, drugallergies, insect sting allergies and food allergies, (2) inflammatorybowel diseases, such as Crohn's disease, ulcerative colitis, ileitis andenteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses suchas dermatitis, eczema, atopic dermatitis, allergic contact dermatitisand urticaria, (5) vasculitis, (6) spondyloarthropathies, (7)scleroderma, (8) asthma and respiratory allergic diseases such asallergic asthma, allergic rhinitis, allergic conjunctivitis,hypersensitivity lung diseases and the like, and (9) autoimmunediseases, such as arthritis (including rheumatoid and psoriatic),systemic lupus erythematosus, type I diabetes, glomerulonephritis andthe like, (10) graft rejection (including allograft rejection andgraft-v-host disease), (11) other diseases in which undesiredinflammatory responses are to be inhibited, e.g., atherosclerosis,myositis, neurological disorders such as stroke, ischemic reperfusioninjury, traumatic brain injury and closed-head injuries,neurodegenerative diseases (e.g., Parkinson's disease), multiplesclerosis, Alzheimer's disease, encephalitis, meningitis, osteoporosis,gout, hepatitis, nephritis, gall bladder disease, sepsis, sarcoidosis,conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitisand Behcet's syndrome; (12) cell proliferative or neoplastic diseasessuch as cancers of the breast, skin, prostate, cervix, uterus, ovary,testes, bladder, lung, liver, larynx, oral cavity, colon andgastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood and lymphatic system and diseases in which angiogenesisand neovascularization play a role; (13) metabolic disorders that aresensitive to inhibition of TNF or IL-1 signaling, such as obesity, typeII diabetes, Syndrome X, insulin resistance, hyperglycemia,hyperuricemia, hyperinsulinemia, cachexia, hypercholesterolemia,hyperlipidemia, dyslipidemia, mixed dyslipidemia andhypertriglyceridemia, eating disorders, such as anorexia nervosa andbulimia, (14) infectious diseases, e.g., bacteremia and septic shock;(15) cardiovascular disorders, such as acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis and vascular stenosis; and (16) immune diseases orconditions.

In one embodiment, the present methods are directed to the treatment orprevention of diseases or conditions selected from rheumatoid arthritis,septic shock, inflammatory bowel disease, bone mass loss, cancer, dermalsensitization disorders, diabetes, obesity, ischemic stroke, ischemicreperfusion injury, closed-head injuries, asthma, allergic disease,multiple sclerosis and graft rejection.

In another embodiment, the present invention provides methods oftreating or preventing a disease or condition responsive to IKKmodulation, comprising administering to a subject having such a diseaseor condition, a therapeutically effective amount of one or more of thesubject compounds or compositions.

In still another embodiment, the present invention provides methods oftreating or preventing a disease or condition mediated by IKK,comprising administering to a subject having such a disease orcondition, a therapeutically effective amount of one or more of thesubject compounds or compositions.

In another embodiment, the present invention provides methods ofmodulating IKK comprising contacting a cell with a compound of theinvention.

In still other embodiments, the present invention provides methods oftreating or preventing a disease or condition responsive to IRAKmodulation, comprising administering to a subject having such a diseaseor condition, a therapeutically effective amount of one or more of thesubject compounds or compositions.

In still another embodiment, the present invention provides methods oftreating or preventing a disease or condition mediated by IRAK,comprising administering to a subject having such a disease orcondition, a therapeutically effective amount of one or more of thesubject compounds or compositions.

In yet another embodiment, the present invention provides methods ofmodulating IRAK comprising contacting a cell with a compound of theinvention.

Depending on the disease to be treated and the subject's condition, thecompounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection orimplant), inhalation, nasal, vaginal, rectal, sublingual transdermal ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The present invention alsocontemplates administration of the compounds of the present invention ina depot formulation, in which the active ingredient is released over adefined time period.

In the treatment or prevention of the above-described diseases andconditions, an appropriate dosage level will generally be about 0.001 to100 mg per kg patient body weight per day which can be administered insingle or multiple doses. Preferably, the dosage level will be about0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg perday, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day.Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to5.0 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Combination Therapy

The compounds of the invention may be combined and/or used incombination with other agents useful in the treatment or prevention ofinflammation, metabolic disorders, infection, cancer and thosepathologies noted above. In many instances, administration of thesubject compounds or pharmaceutical compositions in conjunction withthese alternative therapeutic agents enhances the efficacy of suchagents. Accordingly, in some instances, the compounds of the invention,when combined or administered in combination with, e.g.,antiinflammatory agents, can be used in dosages which are less than theexpected amounts when used alone, or less than the calculated amountsfor combination therapy.

Likewise, compounds and compositions of the invention may be used incombination with other drugs that are used in the treatment, prevention,suppression or amelioration of the diseases or conditions for whichcompounds of the invention are useful. Such other drugs may beadministered, by a route and in an amount commonly used therefor,simultaneously or sequentially with a compound of the invention. When acompound of the invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the invention is preferred. Accordingly, thepharmaceutical compositions of the invention include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound of the invention.

Examples of therapeutic agents or active ingredients that may becombined with a compound of the invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) VLA-4 antagonists, (b) corticosteroids, such asbeclomethasone, methylprednisolone, betamethasone, prednisone,prenisolone, dexamethasone, fluticasone and hydrocortisone, andcorticosteroid analogs such as budesonide; (c) imrunosuppressants suchas cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus(FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (d) antihistamines (H1-histamine antagonists) such asbromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as β2-agonists (e.g., terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (e.g., zafirlukast, montelukast, pranlukast,iralukast, pobilukast and SKB-106,203), leukotriene biosynthesisinhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatoryagents (NSAIDs) such as propionic acid derivatives (e.g., alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid andtioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin,alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac,tolmetin, zidometacin and zomepirac), fenamic acid derivatives (e.g.,flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid andtolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisaland flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam andtenoxican), salicylates (e.g., acetyl salicylic acid and sulfasalazine)and the pyrazolones (e.g., apazone, bezpiperylon, feprazone,mofebutazone, oxyphenbutazone and phenylbutazone) and cyclooxygenase-2(COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®);(g) inhibitors of phosphodiesterase type IV; (h) opiod analgesics suchas codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone,morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine,butorphanol, dezocine, nalbuphine and pentazocine; (i) cholesterollowering agents such as HMG-CoA reductase inhibitors (e.g., lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin and other statins),bile acid sequestrants (e.g., cholestyramine, colestipol anddialkylaminoalkyl derivatives of a cross-linked dextran), vitamin B₃(nicotinic acid or niacin), vitamin B₆ (pyridoxine), vitamin B₁₂(cyanocobalamin), fibric acid derivatives (gemfibrozil, clofibrate,fenofibrate and benzafibrate), probucol, nitroglycerin, inhibitors ofcholesterol absorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors, e.g., melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors, squalene syntetaseinhibitors; 0); anti-diabetic agents such as insulin or insulinmimetics, sulfonylureas (e.g., glyburide, meglinatide, tolbutamide andglipizide), biguanides, e.g., metformin (Glucophage®), α-glucosidaseinhibitors (acarbose), thiazolidinone compounds, e.g., rosiglitazone(Avandia®), troglitazone (Rezulin®), ciglitazone pioglitazone (Actos®)and englitazone; (k) preparations of interferon beta (interferon β-1 α,interferon β-1 β); (1) gold compounds such as auranofin andaurothioglucose, (m) etanercept (Enbrel®); (n) antibody therapies suchas orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®),infliximab (Remicade®) and D2E6 TNF antibody, (o) agents that directlyor indirectly interfere with cytokine signalling, such as soluble TNFreceptors, TNF antibodies and soluble IL-1; (p) IL-1 receptorantagonists, e.g., anakinra (Kineret®); (q) lubricants or emollientssuch as petrolatum and lanolin, keratolytic agents, vitamin D₃derivatives (e.g., calcipotriene and calcipotriol (Dovonex®)), PUVA,anthralin (Drithrocreme®), etretinate (Tegison®) and isotretinoin; (r)multiple sclerosis therapeutic agents such as interferon β-1β(Betaseron®), interferon β-1α (Avonex®), azathioprine (Imurek®,Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid (e.g.,prednisolone) and cyclophosphamide; (s) anti-obesity agents such asfenfluramine, dexfenfluramine, phentermine, sibutramine,gastrointestinal lipase inhibitors (e.g., orlistat),phenylpropanolamine, diethylprorion, mazindol, β3 adrenergic receptoragonists, leptin or derivatives thereof and neuropeptide Y antagonists(e.g., NPY5); (t) other IKK inhibitors, especially IKKα inhibitors; (u)antineoplastic agents, such as DNA alkylating agents (e.g.,mechlorethamine, chlorambucil, cyclophosphamide, melphalan andifosfamide), antimetabolites (e.g., methotrexate, azathioprine,6-mercaptopurine, 5-fluorouracil, cytarabine and gemcitabine),microtubule disruptors and/or spindle poisons (e.g., vinblastine,vincristine, vinorelbine, colchicine, nocodazole, paclitaxel, docetaxel,etoposide, irinotecan and topotecan), DNA intercalators (e.g.,doxorubicin, daunomycin, bleomycin, mitomycin, cisplatin andcarboplatin), nitrosoureas (e.g., carmustine and lomustine), interferon,aspariginase and hormones (e.g., tamoxifen, leuoprolide, flutamide andmegestrol acetate); (v) antithrombotic agents such as thrombolyticagents (e.g., streptokinase, alteplase, anistreplase and reteplase),heparin, hirudin and warfarin derivatives, β-blockers (e.g., atenolol),β-adrenergic agonists (e.g., isoproterenol), ACE inhibitors,vasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride,nitroglycerin and enaloprilat); (w) recombinant tissue plasminogenactivator (tPA); (x) cholinesterase inhibitors, such as galantamine(Reminyl®), donepezil hydrochloride (Aricept®) and rivastigmine(Exelon®); (y) anticholinergic agents (e.g., diphenhydramine,orphenadrine, amitriptyline, doxepin, imipramine, nortriptyline,benztropine, biperiden, ethopropazine, procyclidine andtrihexyphenidyl), dopaminergic agents (e.g., carbidopa/levodopa,bromocriptine and pergolide), selegiline and amantadine; and (z) othercompounds such as 5-aminosalicylic acid; and prodrugs thereof. Inpreferred embodiments, the second agent is selected from prednisone,dexamethasone, beclomethasone, methylprednisone, betamethasone,hydrocortisone, methotrexate, cyclosporin, rapamycin, tacrolimus, anantihistamine, a TNF antibody, an IL-1 antibody, a soluble TNF receptor,a soluble IL-1 receptor, a TNF or IL-1 receptor antagonist, anon-steroidal antiinflammatory agent, a COX-2 inhibitor, an antidiabeticagent, an anticancer agent, hydroxycloroquine, D-penicillamine,infliximab, etanercept, auranofin, aurothioglucose, sulfasalazine,sulfasalazine analogs, mesalamine, corticosteroids, corticosteroidanalogs, 6-mercaptopurine, interferon β-1β, interferon β-1α,azathioprine, glatiramer acetate, a glucocorticoid and cyclophosphamide.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of theinvention is combined with an NSAID the weight ratio of the compound ofthe invention to the NSAID will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the invention and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

The following examples are offered by way of illustration and are notintended to limit the scope of the invention. Those of skill in the artwill readily recognize a variety of noncritical parameters that could bemodified to yield essentially similar results.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Gemini 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet; br s, broad singlet), couplingconstant(s) in Hertz (Hz) and number of protons. Electron Ionization(EI) mass spectra were recorded on a Hewlett Packard 5989A massspectrometer. Mass spectrometry results are reported as the ratio ofmass over charge, followed by the relative abundance of each ion (inparentheses). In tables, a single m/e value is reported for the M+H (or,as noted, M−H) ion containing the most common atomic isotopes. Isotopepatterns correspond to the expected formula in all cases. Electrosprayionization (ESI) mass spectrometry analysis was conducted on aHewlett-Packard 1100 MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Normally the analyte was dissolved inmethanol at 0.1 mg/mL and 1 microliter (μL) was infused with thedelivery solvent into the mass spectrometer, which scanned from 100 to1500 daltons. All compounds could be analyzed in the positive ESI mode,using 1:1 acetonitrile/water with 1% acetic acid as the deliverysolvent. The compounds provided below could also be analyzed in thenegative ESI mode, using 2 mM NH₄OAc in acetonitrile/water as deliverysolvent. Reverse phase HPLC was carried out using a Rainin Dynamax ModelSD-300 with a Capcell Pak C18 column as the stationary phase and elutingwith acetonitrile:H₂O:0.1% TFA. Detection was carried out using aDynamax UV detector at 254 nM.

Example 1 Preparation of4-Amino-2-phenyl-1-H-imidazole[4,5-c]pyridine-7-carboxylic acid amideTFA salt

4,6-Dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid (8).4,6-Dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid was preparedaccording to the procedure described in U.S. Pat. No. 3,891,660.

4-Amino-6-chloro-5-nitro-pyridine-3-carboxylic acid ethyl ester (9). Toa solution of 4,6-Dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid(15 g, 56.6 mmol) and triethylamine (7.9 mL, 57.3 mmol) indichloromethane (84 mL) at 0° C. was added dropwise ammonia solution indioxane (0.5 M, 113 mL, 56.5 mmol). The mixture was then stirredovernight. Removal of the solvent followed by column chromatography gave9 as a yellow crystalline solid. (7.3 g). ¹H-NMR δ: 1.32 (t, J=7.1 Hz,3H), 4.33 (q, J=7.1 Hz, 2H), 8.06 (s, br, 2H), 8.62 (s, 1H).

4-Amino-6-bis(phenylmethyl)amino-5-nitro-pyridine-3-carboxylic acidethyl ester (10). Dibenzylamine (1.95 mL, 10 mmol), triethylamine (1.37mL, 10 mmol), 4-amino-6-chloro-5-nitro-pyridine-3-carboxylic acid ethylester (2.45 g, 10 mmol) and toluene (73 mL) were combined and heated atreflux over night. The reaction mixture was cooled to room temperatureand filtered through a short column of silica gel (eluting first withdichloromethane then ethyl acetate). The organics were concentrated toprovide 10 as a yellow oil (4.2 g). ¹H NMR (400 MHz, D⁶-DMSO) δ: 1.28(t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.60 (s, 4H), 7.14-7.31 (m,10H), 8.35 (s, br, 2H), 8.54 (s, 1H).

6-Bis(phenylmethyl)amino-4,5-diamino-pyridine-3-carboxylic acid ethylester (11). Sodium borohydride (151 mg, 4.1 mmol) was added to asolution of nickel (II) chloride hydrate (261 mg, 1.1 mmol) in MeOH (26mL). After 30 min. at room temperature, a solution of4-amino-6-bis(phenylmethyl)amino-5-nitro-pyridine-3-carboxylic acidethyl ester (0.9 g, 2.2 mmol) in dichloromethane (5 mL) was addedfollowed by the addition of sodium borohydride (353 mg). The mixture wasstirred over night then filtered through a layer of silica gel. Theorganic was diluted with dichloromethane, washed with brine and driedover sodium sulfate. The organics were filtered, concentrated andpurified by column chromatography (dichloromethane:methanol, 20:1). 11was obtained as a white solid (200 mg). ¹H NMR (400 MHz, D⁶-DMSO) δ:1.26 (t, J=7.1 Hz, 3H), 4.21 (s, 4H), 4.22 (q, J=7.1 Hz, 2H), 4.52 (s,2H), 6.73 (s, 2H), 7.14-7.31 (m, 10H), 8.01 (s, 1H). ESIMS, M/Z, 377(M+1)⁺.

4-Bis(phenylmethyl)amino-2-phenyl-1-H-imidazole[4,5-c]pyridine-7-carboxylicacid ethyl ester (12).6-Bis(phenylmethyl)amino-4,5-diamino-pyridine-3-carboxylic acid ethylester (200 mg, 0.53 mmol) was heated with trimethyl orthobenzoate (5 mL)at 130° C. for 10 h. The excess solvent was removed and residue waspurified by column (dichloromethane). A white solid, 12, was obtained(60 mg). ¹H NMR (400 MHz, d⁶-DMSO) δ: 1.36 (t, J=7.1 Hz, 3H), 4.39 (q,J=7.1 Hz, 2H), 5.30 (s, br, 4H), 7.23-7.35 (m, 10H), 7.40-7.50 (m, 3H),8.14-8.16 (m, 2H), 8.45 (s, 1H). ESIMS, M/Z, 463 (M+1)⁺.

4-Amino-2-phenyl-1-H-imidazole[4,5-c]pyridine-7-carboxylic acid ethylester TFA salt (13).4-Bis(phenylmethyl)amino-2-phenyl-1-H-imidazole[4,5-c]pyridine-7-carboxylicacid ethyl ester (59 mg, 0.13 mmol) was treated with Pd(OH)₂ (15 mg,0.11 mmol) in formic acid (2 mL) and heated at reflux over night.Another portion of Pd(OH)₂ (15 mg, 0.11 mmol) was added to the reaction.The mixture was heated at refluxing overnight. This procedure wasrepeated an additional 3 times until the reaction was complete. Removalof the solvent followed by purification using reverse phase HPLCprovided the TFA salt of 13 (20 mg) as a white solid. ¹H NMR (400 MHz,d⁶-DMSO) δ: 1.37 (t, J=7.1 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 7.50-7.60(m, 3H), 8.20-8.30 (m, 2H), 8.31 (s, 1H). ESIMS, M/Z, 283 (M+1)⁺.

4-Amino-2-phenyl-1-H-imidazole[4,5-c]pyridine-7-carboxylic acid amideTFA salt (14).4-Amino-2-phenyl-1-H-imidazole[4,5-c]pyridine-7-carboxylic acid ethylester TFA salt (20 mg, 0.05 mmol) was treated with 1N NaOH (1 mL) andMeOH (1 mL) and heated at reflux for 1 hr. Solvent was removed and theresidue was acidified to pH 2. The white solid was filtered, dried undervacuum and treated with SOCl₂ (1 mL) and heated at reflux for 1 h.Solvent was then removed and the residue was treated with ammonia indioxane (0.5 M, 2 mL). Removal of solvent and purification by reversephase HPLC provided 14 (10 mg) as a white solid. ¹H NMR (400 MHz,d⁶-DMSO) δ: 7.50-7.60 (m, 3H), 7.80 (s, br, 1H), 8.15-8.35 (m, 4H), 8.75(s, br, 2H). ESIMS, M/Z, 254 (M+1)⁺.

Example 2 Preparation of7-carboxamido-4-amino-2-[3,4,5-trimethoxy]phenyl-thieno[3,2-c]pyridine

2-Bromo-4-chloro-7-cyanothieno[3,2-c]pyridine (15).2-bromo-4-chloro-7-cyanothieno[3,2-c]pyridine, 15 was prepared accordingto the procedure described in U.S. Pat. No. 3,9803,095.

2-Bromo-7-cyano-4-p-methoxybenzylaminothieno[3,2-c]pyridine (16). To astirred solution of 4-methoxybenzylamine (1.2 equiv., 2.4 mmol) andK₂CO₃ (2.4 equiv., 4.8 mmol) in 5 mL anhydrous 1-methyl-2-pyrrolidinonewas added 15 (1 equiv., 2 mmol). The mixture was heated at 130° C. underN₂ for 1.5 h, allowed to cool, and the product precipitated by theaddition of H₂O (5 mL). The mixture was filtered, washed with water, anddried, yielding 16 (1.33 mmol) as a brown solid. ¹H NMR (400 MHz,d⁶-DMSO) δ: 8.75 (1H, t, broad), 8.56 (1H, s), 8.21 (1H, s), 7.43 (2H,d, J=8.6 Hz), 7.04 (2H, d, J=8.6), 4.84 (2H, d, J=5.8), 3.88 (3H, s).

2-Bromo-7-carboxamido-4-amino-thieno[3,2-c]pyridine hydrogensulfate salt(17). 1 mL concentrated H₂SO₄ was added to 16 (250 mg) and the mixturestirred at room temperature for 1.5 h. Approx. 3 mL of ice was added tothe reaction flask. The gray precipitate was filtered and washed withwater to yield 110 mg of the hydrogensulfate salt of 17. ¹H NMR (400MHz, d⁶-DMSO) δ: 8.63 (1H, s), 8.30 (1H, broad s), 8.19 (2H, broad d),8.12 (1H, s), 7.78 (1H, broad s).7-Carboxamido-4-amino-2-[3,4,5-trimethoxy]phenylthieno[3,2-c]pyridine(18). 3,4,5 trimethoxybenzene boronic acid (1.2 equiv., 0.35 mmol) wasadded to a mixture of 17 (1 equiv., 0.3 mmol) and K₂CO₃ (2.5 equiv.,0.75 mmol) in 1 mL DMF and 0.5 mL H₂O. The mixture was degassed for 10min. with N₂, and PdCl₂(dppf):DCM complex was added. The mixture washeated at 85° C. under N₂ for 30 min. The mixture was cooled to ambienttemperature, diluted with water, filtered, and the precipitate purifiedfurther by recrystallization from DMF/H₂O. Filtration and washing withwater and ethanol yielded 18 as a brown solid. ¹H NMR (400 MHz, d⁶-DMSO)δ: 8.65 (1H, s), 8.19(1H, s), 8.14 (1H, broad, s), 7.42 (1H, broad, s),7.28 (1H, s), 7.13 (1H, s), 4.06 (2H, s), 3.88 (1 μl, s).

Example 3 Preparation of4-amino-2-(4-methyl-thiophen-2-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide

4-Amino-2-(4-methyl-thiophen-2-yl)thieno[3,2-c]pyridine-7-carboxylicacid amide (19). 19 was prepared from4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 and4-methyl-2-thiopheneboronic acid according to the general proceduredescribed in Example 2. ¹H NMR (400 MHz, d⁶-DMSO) δ: 2.25 (s, 3H), 7.29(s, 1H), 7.36 (s, 1H), 7.80 (br s, 1H), 8.14 (s, 1H), 8.40 (br s, 1H),8.46 (s, 1H). MS (EI) m/z (M+H⁺) 290.

Example 4 Preparation of4-Amino-2-prop-1-ynyl-thieno[3,2-c]pyridine-7-carboxylic acid amide

3-Cyano-3-thiophen-2-yl-acrylic acid potassium salt (21). To a stirringsolution of thiophene-2-acetonitrile 20 (Aldrich, Milwaukee, Wis.) (80.6g, 0.655 mol) in MeOH (1.3 L) was added glyoxylic acid (63.3 g, 0.688mol). To the reaction solution was added portion-wise over 10 minutespotassium tert-butoxide (77.2 g, 0.688 mol). A nitrogen atmosphere wasapplied, and the solution was brought to reflux. After 6 h, the reactionwas warmed to room temperature, filtered, and washed with copiousamounts of MeOH. After drying under reduced pressure, 100 g of 21 as awhite crystalline solid was obtained.

3-Cyano-3-thiophen-2-yl-acryloyl chloride (22). To a stirring solutionof oxalyl chloride (81.17 mL, 0.93 mol) in CH₂Cl₂ (350 mL) was added3-cyano-3-thiophen-2-yl-acrylic acid potassium salt 21 (100 g, 0.45 mol)portion-wise over 20 min. An additional 250 mL of CH₂Cl₂ were added toassist stirring. The slurry was stirred at room temperature for 30 minand was then filtered. The potassium chloride salts were washed withcopious CH₂Cl₂. Collected organic rinses were combined and solventremoved under vacuum to afford 84.3 g of 22, which was carried on to thenext step without further purification.

3-Cyano-3-thiophen-2-yl-acryloyl azide (23). To a vigorously stirringsuspension of NaN₃ (55 g, 0.85 mol) in 1:1; dioxane:H₂O (200 mL) cooledto 0° C. was added dropwise over 20 min a solution of3-cyano-3-thiophen-2-yl-acryloyl chloride 22 (84.3 g, 0.428 mol) indioxane (150 mL). After stirring at 0° C. for 20 min, the reaction waswarmed to room temperature and stirred for 1 h. To the reaction solutionwas added 600 mL H₂O, thus producing a precipitate which was filtered,washed with H₂O and dried under vacuum to provide pure 85 g of 23.

4-Oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile (24). To astirring solution of diphenyl ether (1.5 L) and trin-butylamine (0.3 L)heated to an equilibrated temperature of 215° C. was dropwise added asolution of 3-cyano-3-thiophen-2-yl-acryloyl azide 23 (85 g, 0.416 mol)in CH₂Cl₂ (340 mL). The temperature was maintained between 210-215° C.during this time. Following addition, the reaction was stirred a further30 min, then allowed to cool to room temperature, during which the pureproduct precipitated from solution. The product was filtered and washedwith copious hexane. Drying the precipitate under vacuum provided 58.4 gof 24. ¹H NMR (400 MHz, D⁶-DMSO) δ 12.36 (s, 1H), 8.27 (s, 1H), 7.81 (d,J=5 Hz, 1H), 7.57 (d, J=5 Hz 1H).

2-Iodo-4-oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile (25). To4-oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile 24 (5 g, 28.4mmol) in a 1:1 solution of acetic acid and DMF (18.4 mL) was addedN-iodosuccinimide (12.8 g, 56.8 mmol). The reaction was warmed to 80° C.and stirred for 21 h. The reaction was diluted 10 fold with water andneutralized with aqueous sodium bicarbonate. The precipitate wasfiltered, washed with water and dried to provide 7.27 g of 25. ¹H NMR(400 MHz, d⁶-DMSO) δ 12.45 (s, 1H), 8.25 (d, J=5 Hz, 1H), 7.77 (s, 1H).

4-Chloro-2-iodo-thieno[3,2-c]pyridine-7-carbonitrile (26). To2-iodo-4-oxo-4,5-dihydro-thieno[3,2-c]pyridine-7-carbonitrile 25 (7.75g, 25.6 mmol) was added POCl₃ (90 mL). The reaction was stirred underreflux overnight. POCl₃ was removed by rotary evaporation followed bysuspension of solids in H₂O (500 mL) and filtration. The solids werewashed with copious amounts of H₂O, saturated bicarbonate solution, andwashed further with H₂O to provide upon drying 7.52 g of 26. ¹H NMR (400MHz, d⁶-DMSO) δ 8.82 (s, 1H), 8.06 (s, 1H).

2-Iodo-4-(4-methoxybenzylamino)-thieno[3,2-c]pyridine-7-carbonitrile(27). To NMP (41.3 mL) and 4-methoxybenzylamine (3.66 mL, 28.1 mmol) wasadded K₂CO₃ (7.76 g, 56.2 mmol) and4-chloro-2-iodo-thieno[3,2-c]pyridine-7-carbonitrile 26 (7.52 g, 23.4mmol). The reaction was heated to 80° C. After 1.5 h, NMP was distilledaway under reduced pressure. The resulting solids were suspended in H₂O(500 mL) and filtered. The product was recrystallized from 350 mL oftoluene to obtain 7.75 g of 27. ¹H NMR (400 MHz, d⁶-DMSO) a 8.58 (t, J=6Hz, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.28 (d, J=9 Hz, 2H), 6.89 (d, J=9Hz, 2H), 4.68 (d, J=6 Hz, 2H), 3.37 (s, 3H).

4-Amino-2-iodo-thieno[3,2-c]pyridine-7-carboxylic acid amide (28). To2-iodo-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 27(3.88 g, 9.21 mmol) was added conc. H₂SO₄ (9.75 mL). The reaction wasstirred for 1 h at room temperature, then quenched by the addition ofice (20 g). The filtered precipitate was washed with H₂O, then suspendedin 30% MeOH—CH₂Cl₂ (30 mL). Triethylamine was added dropwise until thesolids dissolved. The solution was purified by silica gel columnchromatography (eluent: 10 to 20% MeOH in CH₂Cl₂ with 1% NH₄OH additive)to yield 2.6 g of 28. ¹H NMR (400 MHz, d⁶-DMSO) a 8.46 (s, 1H), 7.94 (m,2H), 7.31 (bs, 1H), 7.18 (s, 2H).

4-Amino-2-prop-1-ynyl-thieno[3,2-c]pyridine-7-carboxylic acid amide(29). A flask containing4-amino-2-iodo-thieno[3,2-c]pyridine-7-carboxylic acid amide 28 (0.075g, 0.24 mmol), PdCl₂(PPh₃)₂ (0.014 g, 0.018 mmol), and CuI (0.0034 g,0.018 mmol) in DMF (0.75 mL) and TEA (0.1 mL) was evacuated and purgedto a propyne atomosphere at 760 Torr. The reaction was stirredovernight, then H₂O (10 mL) added. The precipitate was collected driedand purified by silica gel column chromatography (eluent: 10% MeOH, 1%NH₄OH in CH₂Cl₂) to afford 0.039 mg of 29. ¹H NMR (400 MHz, D⁶-DMSO) δ8.53 (s, 1H), 7.90 (bs, 1H), 7.73 (s, 1H), 7.23 (m, 3H), 2.14 (s, 3H).

Example 5 Preparation4-Amino-2-cyclopent-1-enyl-thieno[3,2-c]pyridine-7-carboxylic acid amide

4-(4-Methoxy-benzylamino)-2-(trimethyl-stannanyl)thieno[3,2-c]pyridine-7-carbonitrile(30). To2-Iodo-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile(1.0 g, 2.37 mmol) 27 in N₂ sparged THF (8 mL) was added Pd—Cl₂(PPh₃)₂(0.083 g, 0.12 mmol), then hexamethylditin (0.93 g, 2.84 mmol). Thereaction was stirred at room temperature for 1.5 h. The reactioncontents were diluted with CH₂Cl₂ (24 mL) and filtered. The solventswere then removed by rotary evaporation. Silica gel columnchromotagraphy (eluent: 1:1; Et₂O:hexanes) provided 48 mg of 30. ¹H NMR(400 MHz, CDCl₃) δ 8.32 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.29 (s, 1H),6.93 (d, J=8 Hz, 2H), 5.50 (m, 1H), 4.80 (d, J=5 Hz, 2H), 3.84 (s, 3H),0.46 (s, 9H).

2-Cyclopent-1-enyl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile(32). A solution of degassed THF (9.5 mL) containing4-(4-methoxy-benzylamino)-2-(trimethyl-stannanyl)-thieno[3,2-c]pyridine-7-carbonitrile30 (0.19 g, 0.49 mmol) and trifluoromethanesulfonic acidcyclopent-1-enyl ester 31 (Adah et al., Tetrahedron, 1997, 53, 6747)(0.32 g, 1.46 mmol) was added to a separate flask containing a nitrogensparged suspension of Pd(PPh)₄ (0.041 g, 0.036 mmol), LiCl (0.42 g, 10mmol) in THF (9.5 mL). The suspension was brought to reflux undernitrogen atmosphere for 12 h resulting in consumption of the tinreagent. A three fold volume of 10% ethyl acetate in CH₂Cl₂ was added tothe cooled suspension. After filtration, solvent was removed in vacuo.Silica gel column chromatography (eluent: 2.5-5% ethyl acetate inCH₂Cl₂) followed by vigorous extraction from saturated KF solutionprovided 75 mg of 32. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 7.34 (d,J=8 Hz, 2H), 6.94 (d, J=8 Hz, 2H), 6.90 (s, 1H) 6.20 (t, J=2 Hz, 1H)5.41 (m, 1H), 4.77 (d, J=5 Hz, 2H), 3.84 (s, 3H), 2.74 (m, 2H), 2.60 (m,2H), 2.08 (p, J=7 Hz, 2H).

2-Cyclopent-1-enyl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carboxylicacid amide (33).2-Cyclopent-1-enyl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile32 (0.020 g, 0.055 mmol), crushed KOH (0.10 g) and tert-butanol (1.5 mL)was brought to reflux for 45 minutes. The reaction mixture was dilutedwith CH₂Cl₂ (20 mL) and extracted with H₂O (5 mL). The organic layer wasconcentrated in vacuo to provide 33. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s,1H), 7.34 (d, J=8 Hz, 2H), 6.91 (m, 3H), 6.24 (m, 1H), 5.93 (bs, 2H),5.37 (t, J=5 Hz, 1H), 4.78 (d, J=5 Hz, 2H), 3.83 (s, 3H), 2.73 (m, 2H),2.57 (m, 2H), 2.04 (p, J=7 Hz, 2H).

4-Amino-2-cyclopent-1-enyl-thieno[3,2-c]pyridine-7-carboxylic acid amide(34). To2-cyclopent-1-enyl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carboxylicacid amide 33 (21 mg, 0.055 mmol.) was added TFA (2 mL) and the solutionwas heated to 50° C. for 1 h. Solvents were removed in vacuo. Silica gelcolumn chromotagraphy (eluent: 1 NH₄OH, 7% MeOH in CH₂Cl₂) provided 1.1mg of 34. ¹H NMR (400 MWz, d⁶-DMSO)S 8.46 (s, 1H), 7.89 (bs, 1H), 7.51(s, 1H), 7.24 (bs, 1H), 7.12 (bs, 2H), 6.15 (m,1H), 2.72 (m, 2H), 2.53(m, 2H), 2.01 (p, J=7 Hz, 2H).

Example 6 Preparation of4-amino-2-cyclopentyl-thieno[3,2-c]pyridine-7-carboxylic acid amide

4-Amino-2-cyclopentyl-thieno[3,2-c]pyridine-7-carboxylic acid amide(36). A suspension of4-amino-2-cyclopent-1-enyl-thieno[3,2-c]pyridine-7-carboxylic acid amide34 (prepared in example 6 above) (0.056 g, 0.155 mmol) and 10% palladiumon carbon (5 mol %) in DMF (1 mL) was stirred under H₂ (1 atm) for 20 h.The suspension was diluted with MeOH (10 mL) and filtered. Solvent wasremoved in vacuo. To the crude solid of 35 was added concentrated H₂SO₄(0.25 mL). The purple solution was stirred for 1 h followed by theaddition of ice (2 g). The precipitate was filtered then purified bysilica gel column chromatography (eluent: 10% MeOH, 1% NH₄OH in CH₂Cl₂)and converted to the HCl salt to afford 12.5 mg of 36. ¹H NMR (400 MHz,d⁶-DMSO) δ 8.76 (s, 2H), 8.45 (s, 1H), 8.29 (s, 1H), 7.75 (m, 3H), 3.37(m, 1H), 2.14 (m,2H), 1.72 (m, 6H).

Example 7 Preparation of4-Amino-2-imidazol-1-yl-thieno[3,2-c]pyridine-7-carboxylic acid amide

2-Imidazol-1-yl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile(37). To an oven dried Schlenk tube was added CuI (0.0057 g, 0.030mmol), imidazole (0.097 g, 1.42 mmol), Cs₂CO₃ (0.405 g, 1.25 mmol). Thetube was evacuated and purged to argon 5 times. Under argon, the tubewas supplied with2-iodo-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 27(0.25 g, 0.59 mmol) trans-1,2-cyclohexanediamine (0.014 mL, 0.12 mmol),and dioxane (1 mL). The reaction contents were briefly evacuated and thevessel purged to argon 3 times, then sealed and brought to 110° C. withstirring. After 24 h, 20 mL of CH₂Cl₂ were added to the cooled reaction.The mixture was filtered and solvents removed in vacuo. Silica gelcolumn chromatography (eluent: 3% MeOH in CH₂Cl₂) provided 0.12 g of 37.¹H NMR (400 MHz, d⁶-DMSO) δ 8.57 (t, J=6 Hz, 1H), 8.47 (s, 1H), 8.23(bs, 1H), 8.00 (s,1H), 7.71 (bs, 1H), 7.31 (d, J=8 Hz, 2H), 7.21 (bs,1H), 6.91 (d, J=8 Hz, 2H), 3.74 (s, 3H).

4-Amino-2-imidazol-1-yl-thieno[3,2-c]pyridine-7-carboxylic acid amide(38). To2-imidazol-1-yl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile37 (0.050 g, 0.14 mmol) was added H₂SO₄ (0.25 mL). After stirring atroom temperature for 1 h, 2 g of ice were added to the solution. Theprecipitate was filtered, washed with H₂O, then dissolved in 30%methanol, 2.5% triethylamine in CH₂Cl₂. The solution was concentrated,the solid was suspended in H₂O, then filtered and rinsed with H₂Oresulting in pure 38. ¹H NMR (400 MHz, d⁶-DMSO),5 8.57 (s,1H), 8.17 (s,1H), 8.02 (bs, 1H), 7.77 (s,1H), 7.67 (bs, 1H), 7.39 (bs, 1H), 7.18 (m,3H).

Example 8 Preparation4-Amino-2-pyrrolidin-1-yl-thieno[3,2-c]pyridine-7-carboxylic acid amide

4-Amino-2-pyrrolidin-1-yl-thieno[3,2-c]pyridine-7-carboxylic acid amide(39). To an oven dried, nitrogen flushed flask was added Pd₂(dba)₃(0.011 g, 0.012 mmol), BINAP (0.015 g, 0.024 mmol). Dry THF (2 mL) wasadded and the mixture stirred at room temperature for 10 min. A solutionof 2-iodo-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile27 (0.25 g, 0.59 mmol) in THF (3.5 mL) was added followed by addition ofpyrrolidine (0.059 mL, 0.712 mmol) and Cs₂CO₃ (0.27 g, 0.83 mmol). Themixture was briefly sparged with nitrogen, then heated at 65° C. for 15h. The cooled reaction mixture was diluted with CH₂Cl₂ (15 mL) andextracted with saturated aqueous NH₄Cl. The organics were dried withNa₂SO₄ and rapidly flashed through a plug of silica gel (eluent: 5-10%ethyl acetate in toluene). The concentrated crude product was dissolvedin H₂SO₄ and stirred for 1 h at room temperature. Ice (2 g) was added tothe solution and the filtered solution was brought to pH 11 with 50%NaOH. The precipitate was filtered to provide 16 mg of 40. ¹H NMR (400MHz, d⁶-DMSO) δ 8.23 (s,1H), 7.78 (s, 1H), 7.35 (s, 1H), 6.53 (s, 2H),6.08 (s, 1H), 3.30 (t, J=6.5 Hz, 4H), 2.03 (p, J=3 Hz, 4H).

Example 9

3-(2-Phenyl-thiazolo-5-yl)acrylic acid (42).2-phenyl-thiazole-5-carbaldehyde 41 (Silberg A. et al. Chem. Ber. 1964,97, 1684-1687) (3.1 g, 16.4 mmol) was treated with malonic acid (2.4 g,23.0 mmol), pyridine (3 mL) and piperidine (0.16 mL) and the mixture washeated at reflux for 6 hours before being cooled to room temperature.The mixture was then poured into water (50 mL) with stirring. Theresulted yellow solid 42 was filtered, washed with water and air-dried(2.45 g). ¹H NMR (400 MHz, D⁶-DMSO) δ: 6.25 (d, J=15.7 Hz, 1H), 7.53 (m,3H), 7.78 (d, J=15.7 Hz, 1H), 7.97 (m, 2H), 8.23 (s, 1H).

3-(2-Phenyl-thiazolo-5-yl)acryloyl azide (43). To a solution of3-(2-phenyl-thiazolo-5-yl)acrylic acid 42 (1.75 g, 7.6 mmol) and Et₃N(1.40 mL, 9.9 mmol) in acetone (20 mL) at 0° C. was added dropwiseClCO₂Bu^(i) (1.3 mL, 9.9 mmol). After stirring for 1 h at 0° C., NaN₃(643 mg, 9.9 mmol) in water (5 mL) was added and the resulted mixturewas stirred at 0° C. for a further 30 min and then at rt for 30 minbefore the addition of water (100 mL). Filtration gave 43 as a yellowsolid, which was washed with water and air-dried (1.85 g). ¹H NMR (400MHz, d⁶-DMSO) δ: 6.40 (d, J=15.6 Hz, 1H), 7.54 (m, 3H), 7.99 (m, 2H),8.02 (d, J=15.6 Hz, 1H), 8.39 (s, 1H).

2-Phenyl-5H-thiazolo[4,5-c]pyridin-4-one (44). To a stirred mixture ofphenyl ether (20 mL) and ^(n)Bu₃N (5 mL) at 230° C. was added dropwise asolution of 3-(2-phenyl-thiazolo-5-yl)acryloyl azide 43 (1.35 g, 5.26mmol) in dichloromethane (10 mL). The addition rate was controlled suchthat the internal temperature remained above 190° C. After addition, theresulting brown solution was stirred for 30 min before being cooled tort. Hexane (50 mL) was added and the yellow solid was filtered, washedwith hexane and dried in the air to afford 44 (0.85 g). ¹H NMR (400 MHz,D⁶-DMSO) δ: 6.98 (d, J=6.9 Hz, 1H), 7.37 (d, J=6.9 Hz, 1H), 7.55 (m,3H), 8.01 (m, 2H), 11.76 (br s, 1H). MS (EI) m/z (M+H⁺) 229.

7-Bromo-2-phenyl-5H-thiazolo[4,5-c]pyridin-4-one (45). A solution of2-phenyl-5H-thiazolo[4,5-c]pyridin-4-one 44 (400 mg, 1.75 mmol) inacetic acid (5 mL) at rt was treated with bromine (320 mg, 1.93 mmol)and the resulting mixture was heated at reflux for 30 min. After coolingto rt, water (20 mL) was added to the mixture. The yellow solid whichformed was filtered, washed with water and dried in the air to afford 45(527 mg). ¹H NMR (400 MHz, d⁶-DMSO) δ: 7.57 (m, 3H), 7.70 (s, 1H), 8.05(m, 2H). MS (EI) m/z (M+H⁺) 308.

4-Chloro-2-phenyl-thiazolo[4,5-c]pyridine-7-carbonitrile (47). A mixtureof 7-bromo-2-phenyl-5H-thiazolo[4,5-c]pyridin-4-one 5 (515 mg, 1.68mmol) and CuCN (331 mg, 3.70 mmol) in DMF was heated at reflux for 10hours before cooling to rt. A solution of FeCl₃ (3.32 g, 20 mmol) inconcentrated HCl (0.9 mL) and water (5.2 mL) was then added to decomposethe copper complex. The mixture was stirred at 70° C. for 15 min andthen allowed to cool to rt. Water (35 mL) was added and a yellow solid 6was formed which was filtered, washed with water and dried in the air(380 mg).4-oxo-2-phenyl-4,5-dihydro-thiazolo[4,5-c]pyridine-7-carbonitrile 46 wastreated with POCl₃ (5 mL) and the mixture heated at reflux for 4 hours.The solvent was removed under reduced pressure and the residue waspartitioned between dichloromethane and aqueous sodium bicarbonatesolution. The organics were separated and dried over sodium sulfate.Removal of solvent followed by silica gel column chromatography (eluent:dichloromethane) gave white solid 47 (255 mg). ¹H NMR (400 MHz, d⁶-DMSO)δ: 7.61 (m, 3H), 8.21 (m, 2H), 8.93 (s, 1H). MS (EI) m/z (M+H⁺) 272.

4-(4-Methoxy-benzylamino)-2-phenyl-thiazolo[4,5-c]pyridine-7-carbonitrile(48). A mixture of4-chloro-2-phenyl-thiazolo[4,5-c]pyridine-7-carbonitrile 47 (54.2 mg,0.2 mmol) and potassium carbonate (66 mg, 0.48 mmol) in NMP (1 mL) wastreated with 4-methoxybenzylamine (32.5 μL, 2.4 mmol) and the mixturestirred at 130° C. for 8 hours. Silica gel column chromatography(eluent: dichloromethane and ethyl acetate (10 to 1)) afforded 48 as apale yellow solid (70 mg). ¹H NMR (400 MHz, d⁶-DMSO) δ: 3.71 (s, 3H),4.72 (d. J=5.9 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H),7.60 (m, 3H), 8.15 (m, 2H), 8.47 (s, 1H), 8.84 (t, J=6.1 Hz, 1H). MS(EI) m/z (M+H⁺) 373.

7-Carboxamido-4-amino-2-phenyl-thiazolo[4,5-c]pyridine (49).4-(4-methoxy-benzylamino)-2-phenyl-thiazolo[4,5-c]pyridine-7-carbonitrile48 (70 mg, 0.19 mmol) was treated with polyphosphoric acid (2 mL) andthe mixture was heated at 110° C. for 2 hours. After cooling to rt,water (10 mL) was added and the resulting solid was filtered. Thefiltrate was neutralized with 4M NaOH solution. The white solid formedwas filtered, washed with water and dried in the air affording 49 (46mg). ¹H NMR (400 MHz, d⁶-DMSO) δ: 7.30 (s, 2H), 7.42 (br s, 1H), 7.56(m, 3H), 8.04 (br s, 1H), 8.14 (m, 2H), 8.59 (s, 1H). MS (EI) m/z (M+H⁺)271.

Example 10 Preparation of7-amino-2-phenyl-thieno[2,3-c]pyridine-4-carboxylic acid amide

7-Amino-2-phenyl-thieno[2,3-c]pyridine-4-carboxylic acid amide (51). 51was synthesized from 5-phenyl-thiophene-3-carbaldehyde 50 (Gjoes et al.Acta Chem Scand 1972, 26, 1851-1858) in a similar manner to theprocedure used in Example 9. ¹H NMR (400 MHz, D⁶-DMSO) δ: 7.04 (s, 2H),7.08 (br s, 1H), 7.45 (m, 1H), 7.53 (m, 2H), 7.78 (m, 3H), 8.34 (s, 1H),8.37 (s, 1H). MS (EI) m/z (M+H⁺) 270.

Example 11 Preparation of4-amino-3-methyl-2-phenyl-thieno[3,2-c]pyridine-7-carboxylic acid amide

3-Methyl-5H-thieno[3,2-c]pyridin-4-one (53). 53 was prepared from3-(4-methyl-thiophen-2-yl)-acrylic acid 52 (Poirier Y. et al. Bull. Soc.Chim. Fr., 1966, 1052-1068) in a similar manner to that described inExample 9. ¹H NMR (400 MHz, d⁶-DMSO) δ: 2.68 (d, J=1.1 Hz, 3H), 6.69 (d,J=7.0 Hz, 1H), 6.87 (d, J=1.1 Hz, 1H), 7.13 (d, J=7.0 Hz, 1H), 10.75 (brs, 1H). MS (EI) m/z (M+H⁺) 166.

4-Amino-3-methyl-2-phenyl-thieno[3,2-c]pyridine-7-carboxylic acid amide(54). A solution of 3-methyl-5H-thieno[3,2-c]pyridin-4-one 53 (1.45 g,8.8 mmol) in acetic acid (25 mL) was treated with bromine (0.5 mL, 9.7mmol). The mixture was then stirred at 100° C. for 30 min. After coolingto rt, water (50 mL) was added. Filtration gave2-bromo-3-methyl-5H-thieno[3,2-c]pyridine-4-one 54 as a yellow solidcontaining approx. 28% of a dibromide species. The crude material wasconverted to 55 using the procedure described in Example 9. ¹H NMR (400MHz, D⁶-DMSO) δ: 2.56 (s, 3H), 6.64 (s, 2H), 7.25 (br s, 1H), 7.50 (m,5H), 7.85 (br s, 1H), 8.50 (s, 1H). MS (EI) m/z (M+H⁺) 284.

Example 12 Preparation of4-amino-2(1H-pyrazol-4-yl)thieno[3,2-c]pyridine-7-carboxylic acid amide

4-Amino-2(1H-pyrazol-4-yl)thieno[3,2-c]pyridine-7-carboxylic acid amide(57). A mixture of 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylicacid amide 17 (100 mg, 0.37 mmol),4-tributylstannyl-1-triphenylmethylpyrazole (380 mg, 0.56 mmol) andtetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) in dioxane(3 mL) by with column chromatography on silica gel (eluent: DCM/MeOH,20/1 to 10/1) gave 56 as a white solid (60 mg). 56 was treated with 50%TFA in dichloromethane (2 mL) for 2 hours at rt. The solvent was thenremoved under reduced pressure and the residue was partitioned betweendichloromethane and sodium bicarbonate solution. The organics were driedand removed. Silica gel column chromatography (eluent: DCM/MeOH, 20/1 to5/1) gave 57 as a white solid (20 mg). ¹H NMR (400 MHz, D⁶-DMSO) δ: 6.97(s, 1H), 7.10 (s, 1H), 7.22 (s, 1H), 7.30 (br s, 2H), 7.72 (s, 1H), 7.81(br s, 1H), 8.15 (br s, 1H), 8.42 (s, 1H). MS (EI) m/z (M+H⁺) 260.

Example 13 Preparation of4-Amino-2-[4-(2-cyanoethyl)-5-methylthiophen-2-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide

3-(2-Methylthiophen-3-yl)-acylonitrile (59). To a solution ofdiethyl(cyanomethyl)phosphonate (1.26 mL, 7.8 mmol) in THF (20 mL) at 0°C. was added dropwise a 0.5 M solution of KN(SiMe₃)₂ in toluene (13.2mL, 6.6 mmol). After 30 min, the resulting solution was added dropwiseto a solution of 2-methyl-3-thiophenecarbaldehyde 58 (Comins D L et al.J. Org. Chem., 1987, 52, 104-109) (756 mg, 6 mmol) in THF (20 mL) at 0°C. The mixture was then stirred at rt for 30 min before being quenchedwith saturated aqueous ammonium chloride solution. The organics wereseparated and the water layer was extracted with EtOAc (2×10 mL). Thecombined organics were washed with brine and dried over MgSO₄. Removalof the solvent followed with silica gel column chromatography (eluent:DCM/hexane, 1/1) gave 59 as a white solid (795 mg).

3-(2-Methylthiophen-3-yl)-propionitrile (60). A solution of3-(2-methylthiophen-3-yl)-acylonitrile 59 (410 mg, 2.8 mmol) in pyridine(4 mL) and EtOH (1 mL) was treated with sodium borohydride (104 mg, 11 1mmol) at rt and then the mixture was heated to 100° C. for 4 hours.After cooling to rt, water was added and the mixture was extracted withEtOAc (2×20 mL). The combined organics were washed with water and driedover MgSO₄. Removal of the solvent followed with silica gel columnchromatography (eluent: DCM/hexane, 1/1) gave 60 as a colorless liquid(370 mg).

3-(5-Bromo-2-methyl-thiophen-3-yl)-propionitrile (61). A solution of3-(2-methylthiophen-3-yl)-propionitrile 60 (320 mg, 2.1 mmol) in aceticacid (5 mL) was treated with bromine (0.12 mL, 2.3 mmol) and the mixturestirred at rt for 1 hour. Water was added and the mixture was extractedwith EtOAc (2×20 mL). The combined organics were washed with water anddried over MgSO₄. Removal of the solvent followed with silica gel columnchromatography (eluent: DCM/hexane, 1/1) gave 61 as a colorless liquid(330 mg).

¹H NMR (400 MHz, CDCl₃) δ: 2.35 (s, 3H), 2.53 (t, J=10.5 Hz, 2H), 2.84(t, J=10.5 Hz, 2H) 6.80 (s, 1H).

4-Amino-2-[4-(2-cyanoethyl)-5-methylthiophen-2-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide (62). 62 was prepared from4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 and3-(5-bromo-2-methyl-thiophen-3-yl)-propionitrile 61 as a white solid ina similar manner to the procedure described in Example 14. ¹H NMR (400MHz, d⁶-DMSO) δ: 2.40 (s, 3H), 2.81 (s, 4H), 7.15 (s, 2H), 7.23 (s, 1H),7.24 (br s, 1H), 7.70 (s, 1H), 7.80 (br s, 1H), 8.46 (s, 1H). MS (EI)m/z (M+H⁺) 343.

Example 14 Preparation of4-amino-2-morpholin-4-ylmethyl-thieno[3,2-c]pyridine-7-carboxylic acidamide

4-(4-Bromo-thiophen-2-ylmethyl)-morpholine (64). To a solution of4-bromothiophene-2-carbaldehyde 63 (Avocado, UK) (1.20 g, 6.3 mmol) inTHF (50 mL) at rt was added dropwise morpholine (0.96 g, 11 mmol). Afterthe reaction was stirred at rt for 5 minutes, NaBH(OAc)₃ (3.18 g, 15mmol) was added in one portion. The resulting mixture was stirred at rtfor 3 h. Ethyl acetate (80 mL) was added and then washed with NaHCO₃ (20mL×2) and brine (20 mL). The organic layer was dried with MgSO₄. Afterthe solvent was evaporated, the residue was purified by silica gelcolumn chromatography to give 64 (1.31 g).

¹H NMR (400 MHz, CDCl₃) δ, 2.50-2.52(m, 4H), 2.67 (s, 2H), 3.72-3.75 (m,4H), 6.87(s, 1H), 7.15 (d, J=1.4 Hz, 1H). MS (EI) m/z (M+H⁺) 263.

4-Amino-2-morpholin-4-ylmethyl-thieno[3,2-c]pyridine-7-carboxylic acidamide (66). To a mixture of 4-(4-bromo-thiophen-2-ylmethyl)-morpholine64 (173 mg, 0.66 mmol), bis(pinacolato)diboron (352 mg, 1.39 mmol.),Pd(PPh₃)₄ (76 mg, 0.07 mmol) and KOAc (194 mg, 2.0 mmol) was addeddegassed DMF (5 mL). The reaction mixture was heated at 120 ⁰ C under N₂for 2 h and then cooled down to room temperature. A solution of4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 (150mg, 0.55 mmol), Pd(PPh₃)₄ (69 mg, 0.06 mmol) and Na₂CO₃ (1.0 mL of a 2Maqueous solution, 3.3 mmol) in DMF (2.0 mL) was added. The resultingmixture was heated at 90 ⁰ C for 1.5 h. The solvent was then removed viavacuum, the residue was dissolved in DMSO (4.0 mL) and the mixturepurified by reverse phase preparative HPLC to give 66 (134 mg). ¹H NMR(400 MHz, CDCl₃) δ, 3.12 (m, 2H), 3.32 (m, 2H), 3.82 (m, 2H), 3.95 (m,2H), 4.62 (s, 2H), 7.75 (s, 1H), 7.81 (br, 1H), 8.09 (s,1H), 8.34 (s,1H), 8.38 (br, 1H), 8.56 (s, 1H), 9.19 (br, 1H), 11.73 (br, 1H). MS (EI)m/z (M+H⁺) 375.

Example 15 Preparation of4-Amino-2-(2,2-dioxo-2,3,3a,7a-tetrahydro-1H-2λ⁶-benzo[c]thiophen-5-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide

4-Amino-2-(2,2-dioxo-2,3,3a,7a-tetrahydro-1H-2λ⁶-benzo[c]thiophen-5-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide (68). To a stirred solution5-bromo-1,3-dihydro-benzo[c]thiophene 2,2-dioxide (160 mg, 0.65 mmol) 67(Salor, Milwaukee, Wis.) in DMSO (1 mL) was added bis(pinacolato)diboron(178 mg, 0.70 mmol), KOAc (159 mg, 1.6 mmol) and Pd(dppf)Cl₂ DCM complex(22 mg, 0.027 mmol). The mixture was degassed with N₂ and heated at 85°C. for 2 h then DMSO (2 mL), H₂O (0.5 mL), K₂CO₃ (223 mg, 1.6 mmol) and4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide H₂SO₄ salt17 (200 mg, 0.54 mmol) were added. The mixture was stirred at 85° C. fora further 12 h then filtered. The residue was washed with DMSO (2 mL)and the filtrate purified by reverse phase preparative HPLC to yield 68as a white solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 8.31 (s, 1H), 8.24 (s,1H),8,19 (bs, 1H), 7.97-7.92 (m, 3H), 7.85 (d, 1H), 4.78 (s, 2H), 4.71 (s,2H).

Example 16 Preparation of4-amino-2-{4-cyanomethyl-2-[2-(1-methyl-pyrrolidine-2-yl)-ethoxy]-phenyl}-thieno[3,2-c]pyridine-7-carboxylicacid amide

4-Bromo-3-hydroxybenzoic acid methyl ester (70). To a suspension ofmethyl 4-amino-3-hydroxybenzoate 69 (21.7 g, 127 mmol) in water (115 mL)at 0° C. was added a solution of sodium nitrite (9.1 g, 127 mmol) inwater (50 mL). The resultant mixture was stirred at 0° C. for 1 h.Meanwhile, copper sulfate pentahydrate (42.4 g, 169 mmol) was dissolvedin water (135 mL) with heating and sodium bromide (26.4 g, 257 mmol) wasadded slowly with stirring. The resultant dark green solution wasstirred for 5 min, and then was treated with a solution of sodiumsulfite (11.3 g, 90 mmol) in water (40 mL). The resultant lime greenslurry was stirred for 5 min, and then cooled by the addition of ice.The ice water was decanted off, carefully avoiding dryness. The residuewas rinsed with water (3×) and the resultant white solid was dissolvedin 115 mL concentrated HBr (115 mL). This acidic copper bromide solutionwas added to the diazonium salt suspension (see above) at 0° C. Theresultant mixture was gradually heated up to 100° C., then stirred atthis temperature for 1 h. Significant foaming was observed. After thistime, the reaction mixture was cooled and brought to pH 4-5 by theaddition of sodium carbonate. EtOAc was added and the mixture wasfiltered. The filtrate was extracted with EtOAc (3×). The organic layerswere dried over Na₂SO₄ and filtered to give 70. ¹H NMR (400 MHz CDCl₃)δ: 3.91 (s, 3H), 5.81 (br s,1H), 7.48 (dd, J=8.5 Hz, 1.4 Hz, 1H), 7.54(d, J=8.5 Hz, 1H), 7.68 (s, 1H). MS (EI) m/z (M−H⁻) 229.

2-Bromo-5-hydroxymethylphenol (71). To a suspension of4-bromo-3-hydroxybenzoic acid methyl ester 70 (6.97 g, 30.2 mmol) indichloromethane (360 mL) at 0° C. was added DIBALH (100 mL of a 1 M intoluene, 100 mmol) portionwise. Significant gas evolution was observed.The resultant mixture was warmed to room temperature and stirred for2.75 h. After this time, the reaction mixture was quenched by theaddition of saturated aqueous sodium potassium tartrate (600 mL) andsaturated aqueous ammonium chloride (100 mL). The resultant biphasicmixture was stirred vigorously for 2 h, and then extracted withdichloromethane (3×). The organic layers were dried over Na₂SO₄ andfiltered, to give 71. ¹H NMR (400 MHz CDCl₃) δ: 1.70 (br s,1H), 4.64 (d,J=4.5 Hz, 2H), 5.55 (br s, 1H), 6.82 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.04(d, J=2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H). MS (EI) m/z (M−H⁻) 201.

2-Bromo-5-bromomethylphenol (72). To a suspension of2-bromo-5-hydroxymethylphenol 71 (5.17 g, 25.5 mmol) in chloroform (100mL) at 0° C. was added a solution of PBr₃ (1.21 g 12.7 mmol) inchloroform (60 mL) over 30 min. The resultant solution was stirred at 0°C. for 1 h, and then was warmed to room temperature and stirred for anadditional 1.75 h. After this time, the reaction mixture was poured intoice water and extracted with dichloromethane (2×). The organic layerswere dried over Na₂SO₄, filtered, and the filtrate was purified bysilica gel chromatography (eluent: dichloromethane:EtOAc, 95:5) to give72. ¹H NMR (400 MHz CDCl₃) δ: 4.40 (s, 2H), 5.52 (s, 1H), 6.85 (dd,J=8.2 Hz, 2.1 Hz, 1H), 7.06 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H).MS (EI) m/z (M−H⁻) 263.

{4-Bromo-3-[2-(1-methyl-pyrrolidine-2-yl)-ethoxy]-phenyl}-acetonitrile(74). A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) washeated at 60° C. for 30 min. The slurry was cooled to room temperatureand treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g,15.7 mmol) in DMF (50 mL). The resultant mixture stirred at roomtemperature for 23 h, and then was diluted with water and extracted withethyl acetate (5×). The organic layers were dried over Na₂SO₄, filtered,and the filtrate was purified by chromatography on silica gel(hexanes:EtOAc, 3:1) to afford impure(4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5mg) in MEOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile73 (100.0 mg), the resulting mixture was stirred at room temperature for10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride inpresence of triethylamine) were added. The reaction mixture was stirredat room temperature overnight. DCM (80 mL) was added and the organicswashed with saturated aqueous NaHCO₃ solution (20 mL) and brine (20 mL).The organic layer was dried with MgSO₄. The residue was purified bysilica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS(EI) m/z (M+H⁺) 324.

4-Amino-2-{4-cyanomethyl-2-[2-(1-methyl-pyrrolidine-2-yl)-ethoxy]-phenyl}-thieno[3,2-c]pyridine-7-carboxylicacid amide (75). 75 was prepared from 74 and4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 in asimilar manner to that described for Example 14. MS (EI) m/z (M+H⁺) 436.

Example 17 Preparation of4-amino-2-[5-(2-cyano-ethyl)-thiophen-3-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide

3-(4-Bromo-thiophen-2-yl)-acrylonitrile (76). A solution ofdiethyl(cyanomethyl)phosphonate (2.1 mL, 12.9 mmol) in anhydrous THF (50mL) was cooled to 0° C. under nitrogen and treated with KN(TMS)₂ (11mmol of a 0.5 M solution in toluene). After stirring for 15 min at 0°C., a solution of 4-bromo-2-thiophenecarboxaldehyde 63 (Aldrich, Wis.)(1.9 g, 10 mmol) in anhydrous THF (50 mL) was added and the resultingmixture was stirred for 30 min at 0° C. Saturated aqueous NH₄Cl solutionwas added and the crude product extracted three times with diethylether.The ether extracts were dried over Na₂SO₄, filtered, and evaporated, andthe product was purified by flash chromatography on a silica gel column(eluent: 5% EtOAc in hexane). The major fractions were combined andconcentrated to give 76 (2.1 g) in 9.3 to 1 ratio of trans to cisisomers as a white solid; For trans isomer: ¹H NMR (400 MHz, D⁶-DMSO) δ:7.90 (s, 1H), 7.77 (d, J=16.5 Hz, 1H), 7.57 (s, 1H), 6.28 (d, J=16.5 Hz,1H); For cis isomer: ¹H NMR (400 MHz, d⁶-DMSO) δ 7.97 (s, 1H), 7.65 (s,1H), 7.57 (d, J=11.1 Hz, 1H), 5.82 (d, J=11.7 Hz, 1H). MS (EI) m/z[(M+H⁺) (⁷⁹Br)] 214 and [(M+H⁺) (⁸¹Br)] 216.

4-Amino-2-[5-(2-cyano-ethyl)-thiophen-3-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide (78). A mixture of 3-(4-bromo-thiophen-2-yl)-acrylonitrile 76(0.33 g, 1.55 mmol), potassium acatete (0.47 g, 4.74 mmol),bis(pinacolato)diboron (0.84 g, 3.3 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol),and DMF (11 mL) was heated at 100° C. under nitrogen for 1 h.4-Amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 (0.28g, 1.0 mmol), 2 M aqueous Na₂CO₃ solution (3.6 mL), and Pd(PPh₃)₄ (0.12g, 0.1 1 mmol) were added. The reaction mixture was then heated at 100°C. under nitrogen until completion of the reaction (approx. 1 h), cooledto room temperature and concentrated in vacuo to approx. half volume.The mixture was diluted with water (20 mL) and the precipitate of 77that formed was collected by filtration, washed with MeOH, and dried.4-amino-2-[5-(cyano-vinyl)-thiophen-3-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide 77 was then dissolved in pyridine (5 mL) and EtOH (1 mL). Tothe resulting solution was added NaBH₄ (0.16 g, 4.1 mmol). The solutionwas then heated at 100° C. until completion of the reaction (approx. 2h) and then concentrated in vacuo. The crude product was purified bysilica gel column chromatography (eluent: 80% of CH₂Cl₂:MeOH:NH₄OH(89:9:1) in CH₂Cl₂). The major fractions were combined and concentratedto give 78 (0.12 g) as a pale-yellow solid. ¹H NMR (400 MHz, d⁶-DMSO) δ:8.48 (s, 1H), 7.90 (br.s, 1H), 7.86 (s, 1H), 7.65 (d, J=1.4 Hz, 1H),7.31 (s, 1H), 7.26 (br s, 1H), 7.12 (s, 2H), 3.17 (t, 2H), 2.92 (t, 2H).MS (EI) m/z (M+H⁺) 329 and (M+Na⁺) 351.

Example 18 Preparation of4-amino-2[4-(2-cyano-ethyl)-5-(3-hydroxy-propyl)-thiophen-2-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide

3-Thiophen-3-yl-propionitrile (80). A mixture of cyanoacetic acid (7.56g, 88.9 mmol), thiophene-3-carbaldehyde 79 (Aldrich, Wis.) (10.97 g,97.8 mmol), ammonium acetate (0.36 g, 4.7 mmol), toluene (89 mL), andpyridine (47 mL) was heated at reflux for 20 h in a flask fitted with aDean-Stark trap and condenser. After evaporation of solvents, a solutionof the residue in CH₂Cl₂ (300 mL) was washed with water, dried overNa₂SO₄, filtered, and evaporated. The crude product was isolated byflash chromatography on a silica gel column using 10% to 20% gradient ofEtOAc in hexane as eluent to afford 3-thiophen-3-yl acrylonitrile (6.38g) in a 1.8 to 1 ratio of trans to cis isomer as a dark brown oil. Theproduct was then dissolved in pyridine (100 mL) and EtOH (20 mL). To theresulting solution was added NaBH₄ (3.57 g, 94.4 mmol). The solution wasthen heated at 100° C. until completion of the reaction approx. (4 h)and concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (eluent: 11% EtOAc in hexane). The major fractionswere combined and concentrated to give 80 (4.03 g) as a yellow liquid.¹H NMR (400 MHz, d⁶-DMSO) δ: 7.50 (dd, J=3.0 and 5.0 Hz, 1H), 7.31 (m,1H), 7.07 (dd, J=1.0 and 5.0 Hz, 1H), 2.89 (m, 2H), 2.81 (m, 2H). MS(EI) m/z (M+H⁺) 138.

3-(2-Bromo-3-yl)-propionitrile (81). To a solution of3-thiophen-3-yl-propionitrile 80 (4.01 g, 29.2 mmol) in DMF (20 mL) wasadded NBS (5.72 g, 32.2 mmol). The mixture was then stirred at roomtemperature until completion of the reaction (approx. 2 h) andconcentrated in vacuo. A solution of the residue in EtOAc (200 mL) waswashed with water, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel columnchromatography (eluent: 11% to 17% gradient of EtOAc in hexane). Themajor fractions were combined and concentrated to give 81 (5.48 g) as ayellow liquid. ¹H NMR (400 MHz, d⁶-DMSO) δ: 7.60 (d, J=5.63 Hz, 1H),7.06 (d, J=5.64 Hz, 1H), 2.82 (m, 4H). MS (EI) m/z [(M+H⁺) (⁷⁹Br)] 215.9and [(M+H⁺) (⁸¹Br)] 218.

3-[2-(3-Hydroxy-prop-1-ynyl)-thiophen-3-yl]-propionitrile (82). To astirred solution of 3-(2-bromo-thiophen-3-yl)-propionitrile 81 (0.5 g,2.31 mmol), CuI (0.04 g, 0.23 mmol), PdCl₂(PPh₃)₂ (0.08 g, 0.12 mmol) inNEt₃ (6 mL) at room temperature was added propargyl alcohol (0.28 mL,4.62 mmole) and the reaction mixture was stirred at 50° C. for 9 h. Themixture was concentrated in vacuo and purified by silica gel columnchromatography (eluent: 50% EtOAc in hexane). The major fractions werecombined and concentrated to give 82 (0.27 g) as a yellow syrup. ¹H NMR(400 MHz, D⁶-DMSO) δ: 7.54 (d, J=5.0 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H),5.37 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 2.93 (t, J=7.0 Hz, 2H),2.84 (t, J=7.0 Hz, 2H). MS (EI) m/z (M−OH⁺) 174.

3-[2-(3-Hydroxy-propyl)-thiophen-3-yl]-propionitrile (83). To a stirredsolution of 3-[2-(3-hydroxy-prop-1-ynyl)-thiophen-3-yl]-propionitrile 82(0.27 g, 1.39 mmol) was dissolved in MeOH (5 mL). To this solution wasadded Pd/C [10% w/w] (0.15 g, 0.14 mmol). The mixture was then stirredunder an atmosphere of hydrogen at room temperature for 4 h thenfiltered through a Celite pad and concentrated in vacuo. Purification bysilica gel column chromatography (eluent: 50% EtOAc in hexane) afforded83 (0.18 g) as a colorless syrup. ¹H NMR (400 MHz, d⁶-DMSO) δ: 7.27 (d,J=5.0 Hz, 1H), 6.94 (d, J=5.0 Hz, 1H), 4.51 (t, J=5.0 Hz 1H), 3.42 (dd,J=6.0 Hz and 11.5 Hz, 2H), 2.82-2.71 (m, 6H), 1.70 (m, 2H). MS (EI) m/z(M+H⁺) 196, (M−OH⁺) 178.

3-[5-Bromo-2-(3-hydroxy-propyl)-thiophen-3-yl]-propionitrile (84). To asolution of 3-[2-(3-hydroxy-propyl)-thiophen-3-yl]-propionitrile 83(0.18 g, 0.9 mmol) in DMF (2 mL) was added NBS (0.18 g, 0.99 mmol). Themixture was then stirred at room temperature for 6 hours and thenconcentrated in vacuo. A solution of the residue in CH₂Cl₂ (80 mL) waswashed with water, dried over Na₂SO₄, filtered, and concentrated invacuo. Purification by silica gel column chromatography (eluent: 50%EtOAc in hexane) afforded 84 (0.08 g). ¹H NMR (400 MHz, d⁶-DMSO) δ: 7.06(s, 1H), 4.53 (t, J=6.0 Hz, 1H), 3.41 (dd, J=6.0 and 11.5 Hz, 2H), 2.75(m, 6H), 1.67 (m, 2H). MS (EI) m/z [(M+H⁺) (⁷⁹Br)] 274, [(M+H⁺) (⁸¹Br)]276, [(M−OH⁺) (⁷⁹Br)] 256 and [(M−OH⁺) (⁸¹Br)] 258.

4-Amino-2[4-(2-cyano-ethyl)-5-(3-hydroxy-propyl)-thiophen-2-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide (85). A mixture of3-[5-bromo-2-(3-hydroxy-propyl)-thiophen-3-yl]-propionitrile 84 (0.08 g,0.3 mmol), potassium acetate (0.09 g, 0.91 mmol), bis(pinacolato)diboron(0.16 g, 0.63 mmol), Pd(PPh₃)₄ (0.023 g, 0.02 mmol), and DMF (2 mL) washeated at 100° C. under nitrogen for 1 h.4-Amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 (0.54g, 0.2 mmol), 2 M aqueous Na₂CO₃ solution (0.7 mL), and Pd(PPh₃)₄ (0.023g, 0.02 mmole) were added. The reaction mixture was then heated at 100°C. under nitrogen for 40 min. then cooled to room temperature andfiltered. The filtrate was concentrated in vacuo and purified by silicagel column chromatography (eluent: CH₂Cl₂:MeOH:NH₄OH (89:9:1) to afford85 (0.02 g) as an yellow solid. ¹H NMR (400 z, D⁶-DMSO) δ: 8.46 (s, 1H),7.90 (br.s, 1H), 7.72 (s, 1H), 7.24 (s, 1H), 7.23 (br.s, 1H), 7.15 (s,2H), 4.56 (t, 1H), 3.47 (dd, J=6.0 and 11.5 Hz, 2H), 2.82 (m, 6H), 1.75(m, 2H). MS (EI) m/z (M+H⁺) 387.

Example 19 Preparation of4-amino-2-[5-(3-cyano-tetrahydro-furan-2-yl)-thiophen-3-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide

2-(4-Bromo-thiophen-2-yl)-tetrahydro-furan-3-carbonitrile (86). Additionof 4-bromo-2-thiophenecarboxaldehyde 63 (Aldrich, Wis.) (1.0 g, 5.23mmol) to a solution of t-BuOK (1 M in THF, 5.23 mL, 5.23 mmol) at 0° C.was followed immediately by the addition of 4-chloro-butyronitrile (0.51mL, 5.3 mmol). After 3 h, the reaction mixture was allowed to warm tothe room temperature and saturated, aqueous NH₄Cl solution was thenadded. The crude reaction mixture was then separated and the aqueousfraction extracted twice with EtOAc. The combined EtOAc extracts weredried over Na₂SO₄, filtered and concentrated in vacuo. Purification bysilica gel column chromatography (eluent: 10% to 20% gradient of EtOAcin hexane) afforded trans-86 (0.3 g) as an yellow liquid. ¹H NMR (400MHz, d⁶-DMSO) δ: 7.68 (d, J=1.5 Hz, 1H), 7.19 (dd, J=1.0 Hz and 1.5 Hz,1H), 5.26 (d, J=7.0 Hz, 1H), 4.04 (m, 1H), 3.96 (m, 1H), 3.44 (m, 1H),2.41 (m, 1H), 2.29 (m, 1H). MS (EI) m/z [(M+H⁺)⁺ (⁷⁹Br)] 258 and[(M+H⁺)⁺ (⁸¹Br)] 260.

4-Amino-2-[5-(3-cyano-tetrahydro-furan-2-yl)-thiophen-3-yl]-thieno[3,2-c]pyridine-7-carboxylicacid amide (87). 87 was prepared from2-(4-bromo-thiophen-2-yl)-tetrahydro-furan-3-carbonitrile 86 and4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 in asimilar manner to that described in Example 18. ¹H NMR (400 MHz,d⁶-DMSO) δ: 8.48 (s, 1H), 7.90 (bs, 1H), 7.89 (s, 1H), 7.77 (s, 1H),7.46 (s, 1H), 7.26 (bs, 1H), 7.12 (s, 2H), 5.30 (d, J=7.49 Hz, 1H), 4.09(m, 1H), 3.99 (m, 1H), 3.44 (m, 1H), 2.49 (m, 1H), 2.33 (m, 1H). MS (EI)m/z (M+H⁺) 371.

Example 20

4-Amino-2-(6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide (89). 89 was prepared from 6-bromotetralone 88 (Fischer, USA)and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 ina similar manner to that described in Example 14. ¹H NMR (400 MHz,d⁶-DMSO) δ: 2.49-2.52 (buried t, 2H), 3.13 (t, J=6.5 Hz, 2H), 3.66 (s,2H), 7.32 (d, J=8.0 Hz, 1H), 7.59 (dd, J=9.5 Hz, 2.0 Hz, 1H), 7.66 (s,1H), 7.65-7.78 (br s, 1H), 8.17-8.23 (br s,1H), 8.28 (s, 1H), 8.44(s,1H), 8.45-8.66 (br s, 2H). MS (EI) m/z (M+H⁺) 338, (2M+H⁺) 675.

Example 21 Preparation of4-Amino-2-(6-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide

4-Amino-2-(6-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide (90). To a suspension of4-amino-2-(6-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide 89 (24.5 mg, 0.07 mmol) in absolute ethanol (4 mL) was addedsodium borohydride (11.5 mg, 0.30 mmol). After 1.25 h at roomtemperature, the reaction mixture was concentrated, partially dissolvedin a mixture of DMSO and MeOH, and filtered. The filtrate was purifiedby reverse phase preparative HPLC to give 90. ¹H NMR (400 MHz, d⁶-DMSO)δ: 1.63-1.74 (m, 1H), 1.87-1.96 (m, 1H), 2.57-2.68 (m, 1H), 2.73-2.81(m, 1H), 2.90-3.02 (m, 2H), 3.93-4.01 (m, 2H), 7.20 (d, J=8.0 Hz, 1H),7.44-7.48 (m, 2H), 7.70-7.83 (br s,1H), 8.26 (s, 2H), 8.41 (s, 1H),8.63-8.83 (br s, 2H). MS (EI) m/z (M+H⁺) 340, (2M+H⁺) 679.

Example 22 Preparation of4-Amino-2-(2-methoxy-thiophen-3-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide

4-Amino-2-(2-methoxy-thiophen-3-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide (92). 92 was prepared from 3-bromo-2-methoxythiophene 91(Zhang, Y.; Hornfeldt, A.-B.; Gronowitz, S.; Stalhandske, C. ActaChemica Scand. 1994, 48, 843-849) and4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide in asimilar manner to that described for Example 14. ¹H NMR (400 MHz,d⁶-DMSO) δ: 4.10 (s, 3H), 7.13 (d, J=6.0 Hz, 1H), 7.28 (d, J=6.0 Hz,1H), 7.69-7.78 (br s,1H), 8.19 (s, 1H), 8.20-8.30 (br s,1H), 8.40 (s,1H), 8.60-8.80 (br s, 2H). MS (EI) m/z (M+H⁺) 306, (2M+H⁺) 611.

Example 23 Preparation of4-Amino-2-(1-methyl-2,2-dioxo-2,3-dihydro-1H-2Δ6-benzo[c]isothiazol-5-yl)-thieno[3,2-c]pyridine-7-carboxylicacid amide

4-Amino-2-(1-methyl-2,2-dioxo-2,3-dihydro-1H-2□6-benzo[c]isothiazol-5-yl)-thieno[3,2-c]pyridine-7-carboxylic acid amide (94).94 was prepared from 5-bromo-1-methyl-1,3-dihydro-benzo[c]isothiazole2,2-dioxide 93 (Skorcz, J. A.; Suh, J. T.; Germershausen, R. L. J.Heterocyclic Chem. 1973, 10, 249-253) and4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 in asimilar manner to that described for Example 14. ¹H NMR (400 MHz,d⁶-DMSO) δ: 3.29 (s, 3H), 4.99 (s, 2H), 7.24-7.29 (m, 1H), 7.59-7.75 (brs,1H), 7.83-7.97 (m, 2H), 8.39 (s, 1H), 8.60 (s, 1H), 8.71-8.90 (br s,1H). MS (EI) m/z (M+H⁺) 375.

Example 24 Preparation of1-(4-Amino-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanone

Bromo-2-oxo-4 dihydrothieno[3,2-c]pyridine (1). Bromo-2-oxo-4dihydrothieno[3,2-c]pyridine, 1 was prepared according to Eloy andDeryckere (Bull. Soc. Chim. Belges, 1970, 79:301-312).

2-Phenyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine (2). Compound 1 (0.43mmol) was dissolved with heating (ca. 85° C.) in DMF (1.5 mL). To thesolution was added phenylboronic acid (0.50 mmol), Pd(dppf)Cl₂CH₂Cl₂(0.075 mmol), K₂CO₃ (0.564 mmol) and H₂O (1.5 mL). The vessel was purgedwith N₂ for 10 min. The solution, under N₂, was heated to 85° C. After 2h, solvents were removed in vacuo. The residue was purified by Si-gelcolumn chromatography (5% MeOH in CH₂Cl₂) to yield 0.074 g. ¹H NMR (400MHz, d⁶-DMSO) δ: 11.49 (s, 1H), 7.88 (s, 1H), 7.77 (d, J=7 Hz, 2H), 7.47(t, J=7 Hz 2H), 7.38 (t, J=7 Hz 1H), 7.29 (t, J=6 Hz, 1H), 6.88 (d, J=7Hz, 1H).

7-Bromo-2-phenyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine (3). To compound2 (3.92 g, 17.24 mmol) in DMF (133 mL) was added NBS (3.37 g, 19.0mmol). The solution was heated to 60° C. After 1 h, the solution volumewas reduced to approximately one half the volume, and the solution waspoured into H₂O (700 mL). The precipitate was filtered, washed withwater, and dried to yield 5.08 g of 3. ¹H NMR (400 MHz, d⁶-DMSO) δ:11.84 (s, 1H), 8.05 (s, 1H), 7.82 (d, J=7 Hz, 2H), 7.61 (s, 1H), 7.48(t, J=7 Hz 2H), 7.4 (t, J=7 Hz, 1H).

7-Bromo-4-chloro-2-phenyl-thieno[3,2-c]pyridine (95). A mixture of7-bromo-2-phenyl-5H-thieno[3,2-c]pyridin-4-one 3 (2.28 g, 7.5 mmol) inphosphorus oxychloride (27 mL) was heated at reflux for 21 h. Thereaction mixture was basified to pH 5-6 by the addition of saturatedaqueous sodium carbonate and extracted with dichloromethane (1×). Theorganic layer was dried over Na₂SO₄, filtered, and the filtrate waspurified by silica gel column chromatography (eluent: hexane:EtOAc,97:3) to give 95.

¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.52 (m, 3H), 7.72-7.78 (m, 3H), 8.28(s, 1H). MS (EI) m/z (M+H⁺) 324.

1-(4-Chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanol (96).7-bromo-4-chloro-2-phenyl-thieno[3,2-c]pyridine 95 (130 mg, 0.40 mmol)was azeotroped to dryness from benzene and dissolved in THF (11 mL).Upon cooling to −78° C., the solution was treated dropwise with n-BuLi(168 μl of a 2.5 M solution in hexane, 0.42 mmol). After 2 min,acetaldehyde (50 μl, 0.89 mmol) was added and the resultant solution wasstirred at −78° C. for 1 h. After this time, the reaction mixture waswarmed to 0° C., quenched with saturated aqueous ammonium chloride andextracted with ethyl acetate (3×). The organic layers were dried overNa₂SO₄, filtered, and the filtrate was purified by silica gel columnchromatography (eluent: hexane:EtOAc, 4:1) to give 96. ¹H NMR (400 MHz,CDCl₃) δ: 1.68 (d, J=6.5 Hz, 3H), 2.29 (bd, 1H), 5.22-5.29 (m, 1H),7.38-7.49 (m, 3H), 7.69 (s, 1H), 7.73-7.78 (m, 2H), 8.13 (s, 1H). MS(EI) m/z (M+H⁺) 290.

1-(4-Chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanone (97). To asuspension of 1-(4-chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanol 96(92 mg, 0.32 mmol) and 168 mg of powdered 4A molecular sieves indichloromethane (35 mL) was added TPAP (11 mg, 0.03 mmol). The resultantmixture was stirred at room temperature for 1 h. After this time, thereaction mixture was diluted with dichloromethane and washed withsaturated aqueous sodium thiosulfate (1×) and saturated aqueous coppersulfate (1×). The organic layer was dried over Na₂SO₄, filtered, and thefiltrate was purified by silica gel column chromatography (eluent:hexane:EtOAc, 17:3) to give 97. ¹H NMR (400 MHz, CDCl₃) δ: 2.79 (s, 3H),7.40-7.53 (m, 3H), 7.75 (s, 1H), 7.78-7.83 (m, 2H), 8.83 (s, 1H). MS(EI) m/z (M+H⁺) 288.

1-(4-Amino-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanone (98). To asuspension of 1-(4-chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanone97 (61 mg, 0.21 mmol) and potassium carbonate (174 mg, 1.26 mmol) in DMF(1.8 mL) was added 4-methoxybenzylamine (85 μl, 0.64 mmol). Theresultant mixture was heated at 50° C. for 6.75 h. After this time, 20mL of a 1:1 mixture of dichloromethane and methanol was added and theresultant slurry was filtered. The filtrate was concentrated and theresidue was dissolved in trifluoroacetic acid (7 mL). The resultantmixture was heated at 55° C. for 2.75 h. After this time, the reactionmixture was concentrated and the residue was purified by silica gelcolumn chromatography (eluent: dichloromethane:MeOH:Et₃N, 98.5:1.5:0.5)to give 98.

¹H NMR (400 MHz, CDCl₃) δ: 2.66 (s, 3H), 5.78-6.15 (br s, 2H), 7.37 (t,J=7.0 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.54 (s, 1H), 8.0 (d, J=3.5 Hz,2H), 8.56 (s, 1H). MS (EI) m/z (M+H⁺) 269.

Example 25 Preparation of4-cyclohexyamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine 7-carboxylicacid amide (103)

7-Cyano-2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (99).7-Cyano-2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine was preparedaccording to the procedure described in U.S. Pat. No. 3,891,660.

7-Cyano-2-(4′-t-butylphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine(100). To a solution of7-cyano-2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (2.0 g, 7.84mmol) in DMF (40 mL) and water (15 mL) was added 4-t-butylphenyl boronicacid (2.1 g, 11.8 mmol), potassium carbonate (1.4 g, 10.1 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.192 g, 0.23 mmol). The resulting mixturewas stirred under nitrogen for 4 h at 80° C. After this time the mixturewas diluted with DMF (20 mL), filtered through celite to removepalladium residues and water (100 mL) added. The precipitated solid wasfiltered, washed thoroughly with water and dried in air by suction atroom temperature providing 1.4 g of 100 which was used without furtheranalysis or purification.

4-Chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101).7-Cyano-2-(4′-t-butylphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine wasdissolved in phosphorus oxychloride (25 mL) and the resulting solutionheated at reflux for 2 h. After this time the mixture was poured intoice and stirred for 1 h. The precipitated solid was filtered and washedwith water, drying by suction in air at room temperature affording 1.05g of 101.

¹H NMR (300 MHz, D⁶-DMSO) δ 8.83 (s, 1H), 8.11 (s, 1H), 7.92 (d, 2H),7.56 (d, 2H), 1.34 (s, 9H).

4-Cyclohexylamino-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine(102). To a solution of4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (0.05 g,0.153 mmol) in DMF was added cyclohexylamine (0.017 g, 0.168 mmol) andpotassium carbonate (0.023 g, 0.168 mmol). The resulting mixture wasstirred under nitrogen at 80° C. for 2 h. After this time the mixturewas partitioned between ethyl acetate (10 mL) and saturated aqueoussodium bicarbonate solution (10 mL), and the organic layer washed withwater and brine, then dried over magnesium sulphate and concentratedunder reduced pressure. Purification by silica gel chromatography(eluent 20% ethyl acetate in hexane) afforded 0.042 g of 102. ¹H NMR(400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.63 (d, 2H), 7.50 (d, 2H), 7.38 (s,1H), 5.14 (bs, 1H), 4.20 (bs, 1H), 2.18 (m, 2H), 1.80 (m, 4H), 1.6-1.12(m, 13H).

4-Cyclohexyamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine 7-carboxylicacid amide (103).4-Cyclohexylamino-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine(0.042 g, 0.11 mmol) was taken up in t-butanol (2 mL) and powderedpotassium hydroxide (0.007 g, 0.12 mmol) was added. The resultingmixture was heated to reflux for 3 h. After that time the mixture wascooled and water added, the resulting solid was filtered, washed withwater and dried to yield 25 mg of 103. ¹H NMR (400 MHz, CDCl₃), δ 8.22(s, 1H), 7.69 (d, 2H), 7.47 (d, 2H), 7.36 (s, 1H), 5.58 (bs, 2H), 5.07(d, 1H), 4.05 (m, 1H), 2.17 (m, 2H), 1.82 (m, 2H), 1.71 (m, 1H), 1.50(m, 2H), 1.36 (s, 9H), 1.30 (m, 3H). MS (EI) m/z (M+H⁺) 408, (2M+H⁺)815.

Example 26

Preparation of 4-phenylamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (104). 104 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andaniline in a similar manner to that described for Example 25. ¹H NMR(400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.70 (m, 4H), 7.51 (s, 1H), 7.47 (d,2H), 7.40 (t, 2H), 7.19 (bs, 1H), 7.16 (t, 1H), 1.28 (s, 9H). MS (EI)m/z (M+H⁺) 402.

Example 27

Preparation of4-(4′-trans-hydroxycyclohexylamino)-2-(4″-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (105). 105 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) and4-trans-hydroxycyclohexylamine in a similar manner to that described forExample 25. ¹H NMR (400 MHz, d⁶ DMSO) δ 8.51 (s, 1H), 8.22 (s, 1H), 7.89(bs, 1H), 7.65 (d, 2H), 7.50 (d, 2H), 7.25 (s, 1H), 7.24 (s, 1H), 4.62(d, 1H), 4.07 (m, 1H), 3.47 (m, 1H), δ 2.0 (m, 2H), 1.90 (m, 2H), 1.41(m, 4H), 1.32 (s, 9H). MS (EI) m/z (M+H⁺) 424.

Example 28

Preparation of4-(2′-trans-hydroxycyclohexylamino)-2-(4″-t-butylphenul)-thieno[3,2-c]pyridine7-carboxylic acid amide (106). 106 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) and2-trans-hydroxycyclohexylamine in a similar manner to that described forExample 25. ¹H NMR (400 MHz, d⁶ DMSO) δ 8.48 (s, 1H), 8.25 (s, 1H), 7.88(bs, 1H), 7.67 (d, 2H), 7.51 (d, 2H), 7.26 (s, 1H), 7.25 (s, 1H), 4.77(d, 1H), 4.03 (m, 1H), 3.52 (m, 1H), 2.00 (m, 2H), 1.70 (m, 2H), 1.35(s, 9H), 1.30 (m, 4H). MS (EI) m/z (M+H⁺) 424.

Example 29

Preparation of4-[2′-(4″-morpholine)ethylamino]-2-(4″-t-butylphenul)-thieno[3,2-c]pyridine7-carboxylic acid amide (107). 107 was prepared from7-cyano-4-chloro-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) and4-(2-aminoethyl)morpholine in a similar manner to that described inExample 25. ¹H NMR (300 MHz, d⁶-DMSO) δ 8.45 (s, 1H), 8.0 (bs, 1H), 7.90(s, 1H), 7.5 (d, 2H), 7.4 (d, 3H), 3.8 (bm), 3.3 (bm, 8H), 1.2 (s, 9H).MS (EI) m/z (M+H⁺) 439, 352.

Example 30

Preparation of4-furfurylamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine 7-carboxylicacid amide (108). 108 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andfurfurylamine in a similar manner to that described in Example 25. ¹HNMR (300 MHz, D⁶-DMSO) δ 8.25 (s, 1H), 8.0 (s, 1H), 7.9 (bs, 1H), 7.4(d, 3H), 7.3 (d, 3H), 6.2 (bs, 2H), 4.55 (d, 2H), 1.1 (s, 9H). MS (EI)m/z (2M+H⁺) 811, (M+H⁺) 406.5

Example 31

Preparation of4-tetrahydrofurfurylamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (109). 109 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andtetrahydrofurfurylamine in a similar manner to that described in Example25. ¹H NMR (300 MHz, d⁶-DMSO) δ 8.4 (s, 1H), 8.3 (s, 1H), 7.7 (d, 2H),7.55 (d, 2H), 4.15 (m, 1H), 3.6-3.8 (m, 4H), 2.0 (m, 1H), 1.90 (m, 2H),1.7 (m, 1H), 1.3 (s, 9H). MS (EI) m/z (2M+H⁺) 819, (M+H⁺) 410, 326.

Example 32

Preparation of4-(4′-hydroxymethylpiperidinyl)-2-(4″-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (110). 110 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) and4-piperidinemethanol in a similar manner to that described in Example25. ¹H NMR (300 MHz, d⁶-DMSO) δ 8.6 (s, 1H), 8.25 (s, 1H), 7.8 (d, 3H),7.65 (bs, 1H), 7.5 (d, 2H), 4.3 (d, 2H), 3.4 (d, 2H), 3.2 (t, 2H), 1.90(d, 2H), 1.4 (m, 2H), 1.35 (s, 9H). MS (EI) m/z (2M+H⁺) 847.5, (M+H⁺)424

Example 33

Preparation of 4-morpholino-2-(4′-t-butylphenyl)thieno[3,2-c]pyridine7-carboxylic acid amide (111). 111 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andmorpholine in a similar manner to that described in Example 25. ¹H NMR(300 MHz, CDCl₃) δ 8.35 (s, 1H), 7.6 (d, 2H), 7.4 (d, 3H), 6.2 (bs, 2H),3.9 (m, 4H), 3.7 (m, 4H), 1.3 (s, 9H). MS (EI) m/z (2M+H⁺) 791.5, (M+H⁺)396.5.

Example 34

Preparation of4-(1′-hydroxymethyl)ethanolamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (112). 112 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) and2-amino-1,3-propanediol in a similar manner to that described in Example25. ¹H NMR 300 MHz, D⁶-DMSO) δ 8.4 (m, 2H), 8.25 (bs, 1H), 7.7 (d, 2H),7.6 (bs, 1H), 7.5 (d, 2H), 4.3 (m, 1H), 3.7 (m, 4H), 1.3 (s, 9H). MS(EI) m/z (2M+H⁺) 799.5, (M+H⁺) 400.5.

Example 35

Preparation of4-(N-cyclohexyl)ethanolamino-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (113). 113 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andN-cyclohexylethanolamine in a similar manner to that described inExample 25. ¹H NMR (300 MHz, d⁶-DMSO) δ 8.65 (s, 1H), 8.05 (m, 1H), 7.7(d, 3H), 7.6 (d, 2H), 4.4 (t, 1H), 3.7 (m, 2H), 3.6 (m, 2H), 1.7-1.9 (m,10H). MS (EI) m/z (M+H⁺) 452.5.

Example 36

Preparation of4-(4′-amidopiperidin-1′-yl)-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (114). 114 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andisonipecotamide in a similar manner to that described in Example 25. ¹HNMR (300 MHz, D⁶-DMSO) δ 8.5 (s, 1H), 8.1 (bs, 1H), 7.7 (d, 3H), 7.5(bs, 1H), 7.4 (d, 2H), 7.3 (bs, 1H), 6.8 (bs, 1H), 4.1 (d, 2H), 3.1 (t,1H), 1.75 (m, 6H), 1.1 (s, 9H). MS (EI) m/z (M+H⁺) 437.

Example 37

Preparation of4-(N-piperazinyl)-2(4′-t-butylphenyl)thieno[3,2-c]pyridine 7-carboxylicacid amide (115). 115 was prepared from4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (101) andpiperazine in a similar manner to that described in Example 25. ¹H NMR(300 MHz, d⁶-DMSO) δ 8.7 (bs, 1H), 8.6 (s, 1H), 8.1 (bs, 1H), 7.7 (m,3H), 7.4 (d, 2H), 3.65 (m, 4H), 1.2 (s, 9H). MS (EI) m/z (2M+H⁺) 789.5,(M+H⁺) 395.5.

Example 38 Preparation of4-(4′-trans-hydroxycyclohexylamino)-2-(4″-ethylsulphonylphenyl)-thieno[3,2-c]pyridine7-carboxylic amide

7-Cyano-2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (99).7-Cyano-2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine was preparedaccording to the procedure described in U.S. Pat. No. 3,891,660.

2-Bromo-4-chloro-7-cyano-thieno[3,2-c]pyridine (116).2-Bromo-7-cyano-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (99) (2.0 g,7.84 mmol) was dissolved in phosphorus oxychloride (60 mL) and theresulting solution heated at reflux for 2 h. After this time the mixturewas poured into ice and stirred for 1 h. The precipitated solid wasfiltered, washed with water and dried (50° C., P₂O₅, in vacuo),affording a brown solid (1.99 g). ¹H NMR (300 MHz, d⁶-DMSO) δ 9.05 (s,1H), 8.21 (s, 1H)

2-Bromo-4-(4′-trans-hydroxycyclohexylamino)-7-cyano-thieno[3,2-c]pyridine(117). To a solution of 2-bromo-4-chloro-7-cyano-thieno[3,2-c]pyridine(116) (1.99 g, 7.27 mmol) in DMF was added4-trans-hydroxycyclohexylamine (1.21 g, 7.98 mmol) and potassiumcarbonate (3.0 g, 21.7 mmol). The resulting mixture was stirred undernitrogen at 70° C. for 2 h. The solvent was removed in vacuo and thebrown solid triturated in water. The brown solid was filtered, washedwith water and dried (50° C., P₂O₅, in vacuo), affording a brown solid(2.73 g). ¹H NMR (300 MHz, d⁶-CDCl₃) δ 8.20 (s, 1H), 7.19 (s, 1H), 5.85(d, 1H), 4.10 (m, 1H), 2.2-1.9 (dd, 4H), 1.5-1.13 (m, 4H)

2-Bromo-4-(4′-trans-hydroxycyclohexylamino)-thieno[3,2-c]pyridine7-carboxylic amide (118).2-Bromo-4-(4′-trans-hydroxycyclohexylamino)-7-cyano-thieno[3,2-c]pyridine(117) (2.73 g, 7.76 mmol) was taken up in t-butanol (70 mL) and powderedpotassium hydroxide (2.2 g, 39 mmol) added. The resulting mixture washeated to reflux for 2 h. After cooling the mixture was diluted withwater (50 mL) and ethyl acetate (200 mL). The organic layer wasseparated, washed with water (50 mL), and dried (magnesium sulphate).Evaporation of the solvent in vacuo gave a yellow solid (2.3 g). ¹H NMR(300 MHz, d⁶-MeOD) δ 8.69 (s, 1H), 7.95 (s, 1H), 4.32 (bm, 1H), 3.84(bm, 1H), 2.4-2.2 (m, 4H), 1.70 (t, 4H)

4-(4′-trans-hydroxycyclohexylamino)-2-(4″-ethylsulphonylphenyl)-thieno[3,2-c]pyridine7-carboxylic amide (119). To a mixture of2-bromo-4-(4′-trans-hydroxycyclohexylamino)-thieno[3,2-c]pyridine7-carboxylic amide (118) (50 mg, 0.14 mmol) in DMF (2 mL) and water (0.2mL) was added 4-ethylsulphonylphenyl boronic acid (43 mg, 0.2 mmol),potassium carbonate (30 mg) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (10 mg, 0.01 mmol). The resulting mixture wasstirred under nitrogen at 100° C. for 1 h. After this time the mixturewas cooled, filtered and purified by preparative HPLC. The desiredfractions were freeze dried to give a white solid (91 mg). ¹H NMR (300MHz, d⁶-MeOD) δ 8.28 (s, 1H), 7.88 (s, 1H), 3.77 (bm, 1H), 3.58 (bm,1H), 3.13 (q, 2H), 2.05 (bm, 4H), 1.64-1.42 (m, 4H), 1.13 (t, 3H). MS(EI) m/z (M+H⁺) 460.

Example 39 Preparation of4-(trans-4′-hydroxycyclohexylamino)-2-(4″-N-morpholinethoxyphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide) (122)

N-(4-bromophenoxyethyl)morpholine (120). To a solution of 4-bromophenol(3.30 g, 20.0 mmol), triphenylphoshine (5.25 g, 20.0 mmol) andN-(2-hydroxyethyl)morpholine (2.51 g, 19.1 mmol) in THF (30 mL) wasadded diisopropyl azodicarboxylate (3.94 mL, 20.0 mmol) over 10 min. Thereaction mixture was stirred at room temperature for 2 h, and thenhydrochloric acid (50 mL, 1N) was added. The mixture was extracted withdiethyl ether (2×50 mL), and then the pH was adjusted to 10 with 2N aq.NaOH. The mixture was then extracted with ethyl acetate (2×50 mL) andthe combined organic layers were dried over MgSO₄ and concentrated underreduced pressure to afford N-(4-bromophenoxyethyl)morpholine (4.54 g,15.9 mmol) as a white solid.

N-(4-pinacolatoboronylphenoxyethyl)morpholine (121). To a solution ofbis-pinacolatodiboron (0.113 g, 0.44 mmol), KOAc (0.140 g, 1.45 mmol)and [1,1′-bis(diphenylphoshpino)ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (0.020 g, cat.) in DMSO (3 mL) at 100° C. wasadded N-(4-bromophenoxyethyl)morpholine (120) (0.126 g, 0.44 mol) inDMSO (3 mL) over 30 min. After a further 4 h, the reaction mixture wascooled, diluted with ethyl acetate (50 mL), and extracted with brine (25mL) and water (2×25 mL). The organic layer was then concentrated underreduced pressure to afford N-(4-pinacolatoboronylphenoxyethyl)morpholine(0.190 g) as a pale brown solid which was used without furtherpurification.

4-(trans-4′-hydroxycyclohexyamino-2-(4″-N-morpholinethoxyphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (122). A solution of4-(trans-4′-hydroxycyclohexylamino)-2-bromothieno[3,2-c]pyridine7-carboxylic acid amide (118), prepared as described in Example 38,(0.040 g, 0.108 mmol), N-(4-pinacolatoboronylphenoxyethyl)morpholine(0.085 g, from above experiment), K₂CO₃ (0.060 g, 0.43 mmol) in DMF (1mL) and water (0.5 mL) was heated to 75° C. After 16 h, the reactionmixture was filtered and purified by preparative HPLC to afford (122) asa white powder after freeze-drying (0.031 g). ¹H NMR (300 MHz, DMSO) 5,1.20-1.52 (m, 4H), 1.84-2.03 (m, 4H), 3.86-4.05 (4H, m), 4.38-4.48 (2H,m), 7.16 (2H, d), 7.60 (1H, br s), 7.71 (2H, d), 8.23 (2H, br s), 8.40(1H, s), 10.21 (1H, br s). Signals for the remaining 8 protons areobscured by the DMSO peak at 3.2-3.6 ppm. MS (EI) m/z (M+H⁺) 497.

Example 40 Preparation of4-(trans-4′-hydroxycyclohexylamino)-2-(4″-methylthiazolethoxyphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (123)

4-(trans-4′-Hydroxycyclohexylamino)-2-(4″-methylthiazolethoxyphenyl)-thieno[3,2-c]pyridine7-carboxylic acid amide (123) was prepared from4-methyl-5-thiazoleethanol and4-(trans-4′-hydroxycyclohexylamino)-2-bromothieno[3,2-c]pyridine7-carboxylic acid amide (118) by a three-step procedure analogous tothat used in Example 39. ¹H NMR (300 MHz, DMSO) 8, 1.18-1.45 (m, 4H),1.78-1.96 (m, 4H), 2.25 (3H, s), 3.14 (2H, t), 3.81 (1H, br s), 4.11(2H, t), 6.99 (2H, d), 7.57 (1H, d), 8.14 (2H, d), 8.13 (2H, br s), 8.35(1H, s), 8.75 (1H, br s). The signal for the remaining proton isobscured by the DMSO peak at 3.2-3.6 ppm.MS (EI) m/z (M+H⁺) 509.

Example 41 Preparation of4-(4′-trans-hydroxycyclohexylamino)-2-[4″-(phenylacetonitrile)phenyl]-thieno[3,2-c]pyridine-7-carboxylicacid amide (126).

1-(4′-Toluenesulfonyl)-1-phenylacetonitrile (124). A solution ofbenzaldehyde (5 g, 47.1 mmol) and tosyl chloride (8.98 g, 47.1 mmol) wascooled to 0° C. A solution of potassium cyanide (3.06 g, 47 mmol) inwater (10 mL) was added dropwise maintaining temperature below 5° C.After addition a white precipitate formed, the mixture was left to stirat room temperature for 30 min. The precipitate was collected byfiltration and recrystallized by taking up inacetone/ethanol/diethyether (2:2:1-200 mL) to the solution was added ice(200 mL) and left to warm overnight. The resulting precipitate wascollected by filtration to give the desired product (12.3 g). ¹H NMR(300 MHz, d¹-CDCl₃) δ: 7.9 (d, 2H), 7.4 (m, 7H), 6.1 (s,1H), 2.5 (s,3H).

1-(4′-Bromophenyl)-1-phenylacetonitrile (125). A mix of1-(4′-toluenesulfonyl)-1-phenylacetonitrile (124) (3 g, 11 mmol) andbromobenzene (5 g, 32 mmol) was cooled to 0° C. and aluminium chlorideadded portionwise. The mixture was then heated to 90° C. for 3 h. Themixture was left to cool and poured onto ice. The mixture waspartitioned between ethyl acetate. The organics were washed withsaturated sodium hydrogencarbonate (2×), brine, dried (MgSO₄) andconcentrated to dryness. The mixture was purified by chromatographyeluting with 5% EtOAc/Hexane to give the desired product (125) (0.77 g).¹H NMR (300 MHz, dl-CDCl₃) δ: 7.5 (d, 2H), 7.4 (m, 5H), 7.25 (d, 2H),5.1 (s, 1H)

4-(4′-trans-Hydroxycyclohexylamino)-2-[4″-(phenylacetonitrile)phenyl]-thieno[3,2-c]pyridine-7-carboxylicacid amide (126). A mixture of 1-(4′-bromophenyl)-1-phenylacetonitrile(125) (0.77 g, 2.8 mmol), potassium acetate (0.83 g, 8.4 mmol),bis(pinacolato)diboron (0.79 g, 3.1 mmol) in dimethylsulfoxide (5 mL)was degassed (argon). To the mix was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (25 mg) and heated to 90° C. for 2 h. Themixture was partitioned between EtOAc/brine (2×), dried (MgSO₄) andconcentrated to dryness. The residue was treated with4-(4′-trans-hydroxycyclohexylamino)-2-bromo-thieno[3,2-c]pyridine-7-carboxylicacid amide (118), prepared as described in Example 38, (0.75 equiv.),potassium carbonate (0.75 equiv.) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (5 mol %) in dimethylformamide (2 mL) and heatedto 80° C. overnight. The mixture was left to cool and partitionedbetween EtOAc/brine (2×), dried (MgSO₄) and concentrated to dryness. Themixture was purified by chromatography eluting with 10% MeOH/DCM to givea mixture which was further purified by reverse phase chromatography togive desired product (0.1 g). ¹H NMR (300 MHz, d⁶-DMSO) δ: 8.5 (s,1H),8.4 (s,1H), 8.0 (d,1H), 7.9 (d, 2H), 7.6 (d,2H), 7.5 (d, 3H), 7.4 (d,1H), 6.0 (s, 1H), 4.0 (m, 2H), 2.0 (m, 4H), 1.4 (m, 4H). MS (EI) m/z(M+H⁺) 483

Example 42

This example provides an assay that is useful in evaluating andselecting a compound that modulates IKK.

Assay Protocol for Measuring IKKβ Enzyme Inhibition

96 well polystyrene microtiter plates were coated with Neutravidin (10μg/mL in PBS, overnight at 4° C.). The coating solution was removed andin 80 μL/well a kinase reaction mixture was added (20 mM Tris-HCl, pH7.5, 10 mM MgCl₂, 2 mM EGTA, 1 mM NaF, 0.5 mM benzamidine, 1 mM DTT,0.1% NP-40, 10 μM ATP, 1 μM of biotinylated substrate peptideKKERLLDDRHDSGLDSMKDEEYEQGK-bio, sequence derived from IκBα). In 10μL/well in DMSO test compounds were added covering a final concentrationrange from 1 nM to 30 μM. Recombinant full-length IKKβ enzyme producedin a baculovirus system in insect cells was added in 10 μL buffercontaining Tris-HCl pH 7.5 20 mM, EGTA 2 mM, benzamidine 0.5 mM, DTT 1mM, NP-40 0.1%, MgCl₂ 10 mM to initiate the kinase reaction. Thereaction mixture was incubated at room temperature for 45 min. Duringthis incubation the substrate peptide gets phosphorylated by IKKβ andgets captured onto the well's surface by Neutravidin. The plate waswashed 3× with 150 μL distilled water to terminate the reaction andremove components of the reaction mixture.

A conventional chemiluminescent ELISA detection technique was initiatedby adding 100 μL/well primary antibody (custom-made monoclonal antibodygenerated to recognize the phosphorylated epitope in the substratepeptide; used at 1:10,000 dilution) premixed with horseradish peroxidase(HRP) conjugated anti-mouse secondary antibody (commercially availablefrom several sources; used at 1:10,000 dilution) in PBS containing 2%BSA. The solution was incubated at room temperature for 40 min on ashaker, then washed 3× with 150 μL of water. 100 μL/well 10× dilutedSuperSignal HRP substrate (from Pierce) was added and after 5 minincubation the chemiluminescent signal was captured by a LabsystemsLuminoSkan luminometer. The point of 50% inhibition of IKKβ enzymeactivity (IC₅₀) was determined by curve fitting with the LSW dataanalysis software (MDL, San Leandro, Calif.).

The compounds provided in Examples 1-25 all displayed IC₅₀ values of 10μM or less in the above assay.

Example 44

This example provides an assay that is useful in evaluating andselecting a compound that modulates IRAK-1 or IRAK-4.

Assay Protocol for Measuring IRAK-1 or IRAK-4 Enzyme Inhibition

96-well polystyrene microtiter plates were coated with neutravidin forIRAK-1 or streptavidin for IRAK-4 (10 mg/mL in PBS, overnight at 4° C.).The coating solution was removed and in 80 μL/well a kinase reactionmixture was added (for IRAK-1: 20 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 2 mMEGTA, 1 mM NaF, 0.5 mM benzamidine, 1 mM DTT, 3 μM ATP, 1 mM ofbiotinylated substrate peptide bio-ARFSRFAGSSPSQSSMVAR, sequence derivedfrom IRAK-1; for IRAK-4: 20 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 2 mM EGTA,1 mM NaF, 0.5 mM benzamidine, 1 mM DTT, 10% glycerol, 10 μM ATP, 1 mM ofbiotinylated substrate peptide bio-RRRVTSPARRS, sequence derived fromGFAP).

At 10 μL/well in DMSO test compounds were added covering a finalconcentration range from 1 nM to 30 μM. Recombinant, full-length IRAK-1or 1-4 enzyme (baculovirus expression system) was added in 10 μL buffercontaining Tris-HCl pH 7.5 20 mM, EGTA 2 mM, benzamidine 0.5 mM, DTT 1mM, MgCl₂ 10 mM and glycerol 10% (IRAK-4 only) to initiate the kinasereaction. The reaction mixture was incubated at room temperature for 60min. on a shaker. During this incubation the substrate peptide is beingphosphorylated by the kinase and gets captured onto the surface of thewells by neutravidin or streptavidin, respectively. The plate was washed3× with 150 μL distilled water to terminate the reaction and removecomponents of the reaction mixture.

A conventional chemiluminescent ELISA detection technique was initiatedby adding 100 μL/well primary antibody (monoclonal antibody YC10,generated to recognize the phosphorylated epitope in the substratepeptide; used at 1:20,000 dilution for IRAK-1 and 1:10,000 dilution forIRA-4) premixed with horseradish peroxidase (HRP) conjugated anti-mousesecondary antibody (commercially available from several sources; used at1:10,000 dilution) in PBS containing 2% BSA. The solution was incubatedat room temperature for 40 min. on a shaker, then washed 3× with 150 μLof water. 100 μL/well 10× diluted SuperSignal HRP substrate (fromPierce) was added and after 5 min. incubation the chemiluminescentsignal was captured by a Labsystems LuminoSkan luminometer. The point of50% inhibition of IRAK-1 or IRAK-4 enzyme activity (IC₅₀) was determinedby curve fitting with the LSW data analysis software (MDL, San Leandro,Calif.).

The compounds provided in Examples 26-42 all displayed IC₅₀ values of 10μM or less in the above assay.

Sequences

IRAK-1 has an N-terminal Flag tag for purification. IRAK-4 has anN-terminal His Tag. An amino acid spacer is between Tag and the kinase.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1-20. (canceled)
 21. A compound having the formula (Ia.1):

or a pharmaceutically acceptable salt, hydrate, solvate or prodrugthereof, wherein R¹ is selected from the group consisting of—C(O)NR^(1a)R^(1b), —C(O)R^(1a), —CH(═NOH), —N(R^(1b))C(O)R^(1a),—SO₂NR^(1a)R^(1b), —SO₂R^(1a), —C(O)N(R^(1a))OR^(1b),—(C₁-C₄)alkylene-N(R^(1b))C(O)R^(1a), —(C₁-C₄)alkylene-C(O)NR^(1a)R^(1b)and heteroaryl; wherein R^(1a) and R^(1b) are selected from hydrogen,(C₁-C₆)alkyl, (C₂-C₄)alkenyl, (C₂-C₆)heteroalkyl, hydroxy(C₁-C₄)alkyl,fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl; and optionally, R^(1a) is attachedto an adjacent ring member relative to the point of attachment of R¹ toform an additional 5- or 6-membered fused ring, or R^(1a) and R^(1b) arecombined with their intervening atoms to form a 3-, 4-, 5- or 6-memberedring; R² is selected from the group consisting of —NR^(2a)R^(2b) and—OH; wherein R^(2a) and R^(2b) are selected from hydrogen, (C₁-C₆)alkyl,(C₂-C₄)alkenyl, (C₂-C₆)heteroalkyl, mono- or di-hydroxy(C₁-C₄)alkyl,fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkoxy, —C(O)-heterocyclo(C₃-C₈)alkyl andC(O)-fluoro(C₁-C₄)alkyl; and optionally, R^(2a) and R^(2b) may becombined with the nitrogen atom to which each is attached to form a 5-,6- or 7-membered ring containing from 1-3 heteroatoms selected from N, Oand S; L is a divalent linkage selected from the group consisting of asingle bond, (C₁-C₄)alkylene, —C(O)—, —C(O)N(R³)—, —SO₂N(R³)—,—C(R³)═C(R⁴)—, —O—, —S— and —N(R³)—; wherein R³ and R⁴ are independentlyselected from the group consisting of hydrogen, (C₁-C₆)alkyl,cyclo(C₃-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl,heterocyclo(C₅-C₈)alkyl, heteroaryl, heteroaryl(C₁-C₄)alkyl andarylhetero(C₁-C₄)alkyl; Q is selected from the group consisting of(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halogen, aryl,aryl(C₁-C₄)alkyl, heteroaryl, cyclo(C₃-C₈)alkyl, cyclo(C₅-C₈)alkenyl andheterocyclo(C₃-C₈)alkyl, wherein each of the moieties is optionallyfurther substituted, X¹, X² and X³ are independently selected from thegroup consisting of ═C—, —CH— and —N—; Y¹, Y², Y³ and Y⁴ areindependently selected from the group consisting of ═C(R^(5a))—,—C(R⁵)(R⁶)—, —C(O)—, ═N—, —N(R⁵)—, —O— and —S(O)_(m)—; Z¹ and Z² areindependently CH, or ═C—; each R³, R⁴, R⁵ and R⁶ is independentlyselected from the group consisting of hydrogen, (C₁-C₆)alkyl,cyclo(C₃-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl,heterocyclo(C₅-C₈)alkyl, heteroaryl, heteroaryl(C₁-C₄)alkyl andarylhetero(C₁-C₄)alkyl; each R^(5a) is independently selected from thegroup consisting of hydrogen, halogen, (C₁-C₆)alkyl, cyclo(C₃-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, hetero(C₁-C₆)alkyl, heterocyclo(C₅-C₈)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl and arylhetero(C₁-C₄)alkyl; and thesubscript m is an integer of from 0 to 2; with the proviso that saidcompound is other than


22. The compound of claim 21, wherein Q is selected from the groupconsisting of phenyl, naphthyl, pyridyl, pyrrolidinyl, pyrazinyl,pyridazinyl, pyrimidyl, quinolyl, tetrahydroquinolyl, isoquinolyl,cyclopentyl and cyclohexyl.
 23. The compound of claim 21, wherein Q isunsubstituted phenyl or phenyl substituted with from 1 to 3 substituentsselected from the group consisting of halogen, cyano, nitro,cyano(C₂-C₆)alkenyl, nitro(C₂-C₆)alkenyl, —R′, —OR′, —NR′R″, —C(O)R′,—CO₂R′, —C(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′C(O)NR″R′″, —S(O)R′,—SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —OC(O)NR′R″, —X—C(O)R′, —X—CO₂R′,—X—C(O)NR′R″, —X—NR″C(O)R′, —X—NR″CO₂R′, —X—NR′C(O)NR″R′″, —X—S(O)′,—X—SO₂R′, —X—SO₂NR′R″, —X—NR″SO₂R′ and —X—OC(O)NR′R″, and optionally R′or R″ is attached to an adjacent ring atom on the phenyl group to form a5- or 6-membered fused ring; wherein X is (C₁-C₆)alkylene; and R′, R″and R′″ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₄)alkenyl, (C₁-C₆)heteroalkyl,hydroxy(C₁-C₄)alkyl, fluoro(C₁-C₄)alkyl, cyano(C₁-C₄)alkyl,cyano(C₁-C₄)haloalkyl, cyclo(C₃-C₈)alkyl, mono- ordi-hydroxycyclo(C₃-C₈)alkyl, heterocyclo(C₃-C₈)alkyl,heterocyclo(C₃-C₈)alkyl-(C₁-C₄)alkyl, aryl, aryl(C₁-C₄)alkyl,heteroaryl, heteroaryl(C₁-C₄)alkyl, —C(O)—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkoxy, —C(O)-heterocyclo(C₃-C₈)alkyl and—C(O)-fluoro(C₁-C₄)alkyl; and optionally, any two of R′, R″ and R′″ canbe combined with their intervening atom(s) to form a 5-, 6- or7-membered ring containing from 1-3 heteroatoms selected from N, O andS.
 24. The compound of claim 21, wherein R¹ is selected from the groupconsisting of —C(O)NR^(1a)R^(1b), —SO₂NR^(1a)R^(1b), —SO₂R^(1a),—C(O)R^(1a), imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl,thienyl and pyridyl.
 25. The compound of claim 21, having the formula(III):


26. (canceled)
 27. The compound of claim 21, having the formula (V):


28. The compound of claim 21, having the formula (VI):


29. The compound of claim 28, wherein R² is —NHR^(2b).
 30. The compoundof claim 28, wherein R¹ is selected from the group consisting of—C(O)NHR^(1a), —SO₂NHR^(1a), —SO₂R^(1a), heteroaryl and —C(O)CH₃ and R²is —NHR^(2b).
 31. The compound of claim 28, wherein R¹ is selected fromthe group consisting of —C(O)NHR^(1a), —SO₂NHR^(1a), —SO₂R^(1a),heteroaryl and —C(O)CH₃, R² is —NHR^(2b) and each R^(5a) is hydrogen.32. The compound of claim 31, selected from the group consisting of:

33-34. (canceled)
 35. A pharmaceutical composition comprising apharmaceutically acceptable carrier, excipient or diluent and a compoundof claim
 21. 36. A method for treating or preventing an inflammatory,metabolic, infectious, cell proliferative or immune disease orcondition, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of claim 21.37. The method of claim 36, wherein said inflammatory, metabolic,infectious, cell proliferative or immune disease or condition isselected from the group consisting of rheumatoid arthritis, inflammatorybowel disease, psoriasis, cancer, diabetes, septic shock, asthma,allergic disease, multiple sclerosis and graft rejection.
 38. The methodof claim 36, wherein said compound is administered orally, topically,intravenously or intramuscularly.
 39. The method of claim 36, whereinsaid compound is administered in combination with a second therapeuticagent selected from the group consisting of prednisone, dexamethasone,beclomethasone, methylprednisone, betamethasone, hydrocortisone,methotrexate, cyclosporin, rapamycin, tacrolimus, an antihistamine, aTNF antibody, an IL-1 antibody, a soluble TNF receptor, a soluble IL-1receptor, a TNF or IL-1 receptor antagonist, a non-steroidalantiinflammatory agent, a COX-2 inhibitor, an antidiabetic agent, ananticancer agent, hydroxycloroquine, D-penicillamine, infliximab,etanercept, auranofin, aurothioglucose, sulfasalazine, sulfasalazineanalogs, mesalamine, corticosteroids, corticosteroid analogs,6-mercaptopurine, interferon β-1β, interferon β-1α, azathioprine,glatiramer acetate, a glucocorticoid and cyclophosphamide.
 40. A methodfor treating or preventing a disease or condition responsive to IKKmodulation, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of claim
 21. 41. A methodfor treating or preventing a disease or condition mediated by IKK,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of claim
 21. 42. A method for modulatingIKK, comprising contacting a cell with a compound of claim
 21. 43. Themethod of claim 42, wherein said compound inhibits IKK.
 44. The methodof claim 42, wherein said compound inhibits IKKβ.
 45. The method ofclaim 42, wherein said compound inhibits IKKβ, and IKKα.
 46. Thecompound of claim 21, selected from the group consisting of: